Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device

ABSTRACT

Embodiments of the invention provide swallowable devices, preparations and methods for delivering drugs and other therapeutic agents within the GI tract. Many embodiments provide a swallowable device for delivering the agents. Particular embodiments provide a swallowable device such as a capsule for delivering drugs into the intestinal wall or other GI lumen. Embodiments also provide various drug preparations that are configured to be contained within the capsule, advanced from the capsule into the intestinal wall and degrade to release the drug into the bloodstream to produce a therapeutic effect. The preparation can be operably coupled to delivery means having a first configuration where the preparation is contained in the capsule and a second configuration where the preparation is advanced out of the capsule into the intestinal wall. Embodiments of the invention are particularly useful for the delivery of drugs which are poorly absorbed, tolerated and/or degraded within the GI tract.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/391,087, filed Apr. 22, 2019, now U.S. Pat. No. ______; which is acontinuation of U.S. patent application Ser. No. 15/716,259 filed Sep.26, 2017, now U.S. Pat. No. 10,314,892; which is a continuation of U.S.patent application Ser. No. 15/009,601, filed Jan. 28, 2016, now U.S.Pat. No. 9,814,763; which is a continuation of U.S. patent applicationSer. No. 13/538,812, filed Jun. 29, 2012, now U.S. Pat. No. 9,259,386;which claims the benefit of priority of Provisional U.S. PatentApplication Ser. No. 61/571,643, filed Jun. 29, 2011; and claims thebenefit of U.S. Provisional Application No. 61/571,641, filed Jun. 29,2011; and U.S. patent application Ser. No. 15/009,601 is also acontinuation-in-part of the following U.S. patent applications: U.S.patent application Ser. No. 12/978,233, filed on Dec. 23, 2010, now U.S.Pat. No. 8,721,620; U.S. patent application Ser. No. 12/978,164, filedon Dec. 23, 2010, now U.S. Pat. No. 8,759,284; and U.S. patentapplication Ser. No. 12/978,301, filed on Dec. 23, 2010, now U.S. Pat.No. 8,562,589; the entirety of which are fully incorporated by referenceherein for all purposes.

This application is also related to Attorney Docket No. 42197-715.201which was filed Jun. 25, 2012, as U.S. application Ser. No. 13/532,589,now U.S. Pat. No. 9,149,617, which is incorporated by reference hereinfor all purposes.

BACKGROUND OF THE INVENTION Field of the Invention

Embodiments of the invention relate to swallowable drug deliverydevices. More specifically, embodiments of the invention relate toswallowable drug delivery devices for delivering drugs to the smallintestine.

While there has been an increasing development of new drugs in recentyears for the treatment of a variety of diseases, many have limitedapplication because they cannot be given orally. This is due to a numberof reasons including: poor oral toleration with complications includinggastric irritation and bleeding; breakdown/degradation of the drugcompounds in the stomach; and poor, slow or erratic absorption of thedrug. Conventional alternative drug delivery methods such as intravenousand intramuscular delivery have a number of drawbacks including pain andrisk of infection from a needle stick, requirements for the use ofsterile technique and the requirement and associated risks ofmaintaining an IV line in a patient for an extended period of time.While other drug delivery approaches have been employed such asimplantable drug delivery pumps, these approaches require thesemi-permanent implantation of a device and can still have many of thelimitations of IV delivery. Thus, there is a need for an improved methodfor delivery of drugs and other therapeutic agents, including a need forimproved delivery of somatostatin or a somatostatin analogue fortreatment of somatostatin-responsive conditions.

BRIEF SUMMARY OF THE INVENTION

Embodiments of the invention provide devices, systems, kits and methodsfor delivering drugs and other therapeutic agents to various locationsin the body. Many embodiments provide a swallowable device fordelivering drugs and other therapeutic agents within theGastrointestinal (GI) tract. Particular embodiments provide aswallowable device such as a capsule for delivering drugs and othertherapeutic agents into the wall of the small intestine or other GIorgan wall. Embodiments of the invention are particularly useful for thedelivery of drugs and other therapeutic agents which are poorlyabsorbed, poorly tolerated and/or degraded within the GI tract. Further,embodiments of the invention can be used to deliver drugs which werepreviously only capable of or preferably delivered by intravenous orother form of parenteral administration including various non-vascularinjected forms of administration such as intramuscular or subcutaneousinjection.

In one aspect of the invention, the invention provides a therapeuticagent preparation for delivery into a wall of the intestinal tract, thepreparation comprises a therapeutically effective dose of at least onetherapeutic agent. The preparation has a shape and material consistencyto be contained in a swallowable capsule or other device and deliveredfrom the capsule into the intestinal wall to release the dose oftherapeutic agent from within the instestinal wall.

In another embodiment, the invention provides a therapeutic agentpreparation for delivery into a wall of the intestinal tract such as thewall of the small intestine, the preparation comprises a therapeuticallyeffective dose of at least one therapeutic agent. The preparation isconfigured to be contained in a swallowable capsule and operably coupledto an actuator, expandable balloon or other device having a firstconfiguration and a second configuration. The preparation is containedwithin the capsule in the first configuration and advanced out of thecapsule and into the intestinal wall in the second configuration todeliver the therapeutic agent into the intestinal wall.

In other embodiments, the invention provides a method for delivering atherapeutic agent into the wall of the small intestine comprisingswallowing a drug delivery device comprising a capsule, an actuator andan embodiment of the therapeutic agent preparation. The actuator isresponsive to a condition in the small intestine such as pH so as toactuate delivery of the therapeutic agent preparation into the wall ofthe small intestine. In specific embodiments, the actuator can comprisea release element or coating on the capsule which is degraded by aselected pH in the small intestine. Once degraded, the element orcoating initiates delivery of the therapeutic agent preparation by oneor more delivery means such as the by expansion of one or more balloonsthat are operably coupled to tissue penetrating members that contain thetherapeutic agent preparation and are configured to penetrate and beadvanced into the intestinal wall upon expansion of the balloon. Oncethe tissue penetrating members are in the intestinal wall, they degradeto release the therapeutic agent into the bloodstream. Because thetherapeutic agent preparation is delivered directly into the wall of thesmall intestine, the time period (described herein as C_(max)) forachieving the maximum concentration of the therapeutic agent in thebloodstream or other location in the body is shorter than acorresponding time period for achieving such a maximum concentrationwhen the therapeutic agent is non-vascularly injected into the body suchas by intramuscular or subcutaneous injection. In various embodiments,the time period for achieving C_(max) by insertion of the therapeuticpreparation into the intestinal wall using one or more embodiments ofthe invention (such as an embodiment of the swallowable device) can be80%, 50%, 30%, 20 or even 10% of the time period for achieving a C_(max)through the use of a non-vascular injection of the therapeutic agent. Inother embodiments, the C_(max) achieved by insertion of the therapeuticpreparation into the intestinal wall using one or more embodiments ofthe invention, such as an embodiment of the swallowable device, can begreater than a C_(max) achieved by taking a convention oral form of thetherapeutic agent (e.g., a pill) where the therapeutic agent is notinserted into the intestinal wall. In various embodiments, the C_(max)achieved by insertion of the therapeutic preparation into the intestinalwall using one or more embodiments of the invention (such as anembodiment of the swallowable device) can be 5, 10, 20, 30, 40, 50, 60,70, 80 or even a 100 times greater than when the therapeutic agent isdelivered in a pill or other oral form. In other related embodiments,the composition can be configured to produce a long-term release oftherapeutic agent with a selectable t½, that is the time period requiredfor the concentration of the therapeutic agent in the bloodstream orother location in the body to reach half its original C_(max) valueafter having reached C_(max). For example, the selectable t½ may be 6,or 9, or 12, or 15 or 18, or 24 hours.

In another aspect, the invention provides a swallowable device fordelivering a drug or other therapeutic agent preparation into the wallof the small or large intestine or other organ of the gastro-intestinal(GI) tract. The devise comprises a capsule sized to be swallowed andpass through the gastro-intestinal tract, a deployable alignerpositioned within the capsule for aligning a longitudinal axis of thecapsule with the a longitudinal axis of the small intestine, a deliverymechanism for delivering the therapeutic agent into the intestinal walland a deployment member for deploying at least one of the aligner or thedelivery mechanism. The capsule wall is degradable by contact withliquids in the GI tract but also may include an outer coating or layerwhich only degrades in the higher pH's found in the small intestine, andserves to protect the underlying capsule wall from degradation withinthe stomach before the capsule reaches the small intestine at whichpoint, the drug delivery is initiated by degradation of the coating. Inuse, such materials allow for the targeted delivery of a therapeuticagent in a selected portion of the GI tract such as the small intestine.Suitable outer coatings can include various enteric coatings such asvarious co-polymers of Methacrylic Acid and Ethyl Acrylate.

Another embodiment of the capsule includes at least one guide tube, oneor more tissue penetrating members positioned in the at least one guidetube, a delivery member and an actuating mechanism. The tissuepenetrating member will typically comprise a hollow needle or other likestructure and will have a lumen and a tissue penetrating end forpenetrating a selectable depth into the intestinal wall. In variousembodiments, the device can include a second and a third tissuepenetrating member with additional numbers contemplated. Each tissuepenetrating member can include the same or a different drug. Inpreferred embodiments having multiple tissue penetrating members, thetissue penetrating members can be symmetrically distributed around theperimeter of the capsule so as to anchor the capsule onto the intestinalwall during delivery of drug. In some embodiments, all or a portion ofthe tissue penetrating member (e.g., the tissue penetrating end) can befabricated from the drug preparation itself. In these and relatedembodiments, the drug preparation can have a needle or dart-likestructure (with or without barbs) configured to penetrate and beretained in the intestinal wall.

The tissue penetrating member can be fabricated from variousbiodegradable materials (e.g., PLGA, maltose or other sugars) so as todegrade within the small intestine and thus provide a fail-safemechanism for detaching the tissue penetrating member from theintestinal wall should this component become retained in the intestinalwall. Additionally, in these and related embodiments, selectableportions of the capsule can be fabricated from such biodegradablematerials so as to allow the entire device to controllably degrade intosmaller pieces. Such embodiments facilitate passage and excretion of thedevices through the GI tract. In particular embodiments, the capsule caninclude seams of biodegradable material which controllably degrade toproduce capsule pieces of a selectable size and shape to facilitatepassage through the GI tract. The seams can be pre-stressed, perforatedor otherwise treated to accelerate degradation. The concept of usingbiodegradable seams to produce controlled degradation of a swallowabledevice in the GI tract can also be applied to other swallowable devicessuch as swallowable cameras to facilitate passage through the GI tractand reduce the likelihood of a device becoming stuck in the GI tract.

The delivery member is configured to advance the drug from the capsulethrough the tissue penetrating member lumen and into the intestinalwall. Typically, at least a portion of the delivery member isadvanceable within the tissue penetrating member lumen. The deliverymember can have a piston or like structure sized to fit within thedelivery member lumen. The distal end of the delivery member (the endwhich is advanced into tissue) can have a plunger element which advancesthe drug within tissue penetrating member lumen and also forms a sealwith the lumen. The plunger element can be integral or attached to thedelivery member. Preferably, the delivery member is configured to travela fixed distance within the needle lumen so as to deliver a fixed ormetered dose of drug into the intestinal wall. This can be achieved byone or more of the selection of the diameter of the delivery member(e.g., the diameter can be distally tapered), the diameter of the tissuepenetrating member (which can be narrowed at its distal end), use of astop, and/or the actuating mechanism. For embodiments of the devicehaving a tissue penetrating member fabricated from drug (e.g., a drugdart), the delivery member is adapted to advance the dart out of thecapsule and into tissue.

The delivery member and tissue penetrating member can be configured forthe delivery of liquid, semi-liquid or solid forms of drug or all three.Solid forms of drug can include both powder or pellet. Semi liquid caninclude a slurry or paste. The drug can be contained within a cavity ofthe capsule, or in the case of the liquid or semi-liquid, within anenclosed reservoir. In some embodiments, the capsule can include a firstsecond, or a third drug (or more). Such drugs can be contained withinthe tissue penetrating member lumen (in the case of solids or powder) orin separate reservoirs within the capsule body.

The actuating mechanism can be coupled to at least one of the tissuepenetrating member or the delivery member. The actuating mechanism isconfigured to advance the tissue penetrating member a selectabledistance into the intestinal wall as well as advance the delivery memberto deliver the drug and then withdraw the tissue penetrating member fromthe intestinal wall. In various embodiments, the actuating mechanism cancomprise a preloaded spring mechanism which is configured to be releasedby the release element. Suitable springs can include both coil(including conical shaped springs) and leaf springs with other springstructures also contemplated. In particular embodiments, the spring canbe cone shaped to reduce the length of the spring in the compressedstate even to the point where the compressed length of the spring isabout the thickness of several coils (e.g., two or three) or only onecoil.

In particular embodiments the actuating mechanism comprises a spring, afirst motion converter, and a second motion converter and a trackmember. The release element is coupled to the spring to retain thespring in a compressed state such that degradation of the releaseelement releases the spring. The first motion converter is configured toconvert motion of the spring to advance and withdraw the tissuepenetrating element in and out of tissue. The second motion converter isconfigured to convert motion of the spring to advance the deliverymember into the tissue penetrating member lumen. The motion convertersare pushed by the spring and ride along a rod or other track memberwhich serves to guide the path of the converters. They engage the tissuepenetrating member and/or delivery member (directly or indirectly) toproduce the desired motion. They are desirably configured to convertmotion of the spring along its longitudinal axis into orthogonal motionof the tissue penetrating member and/or delivery member thoughconversion in other directions is also contemplated. The motionconverters can have a wedge, trapezoidal or curved shape with othershapes also contemplated. In particular embodiments, the first motionconverter can have a trapezoidal shape and include a slot which engagesa pin on the tissue penetrating member that rides in the slot. The slotcan have a trapezoidal shape that mirrors or otherwise corresponds tothe overall shape of the converter and serves to push the tissuepenetrating member during the upslope portion of the trapezoid and thenpull it back during the down slope portion. In one variation, one orboth of the motion converters can comprise a cam or cam like devicewhich is turned by the spring and engages the tissue penetrating and/ordelivery member.

In other variations, the actuating mechanism can also comprise anelectro-mechanical device/mechanism such as a solenoid or apiezoelectric device. In one embodiment, the piezoelectric device cancomprise a shaped piezoelectric element which has a non-deployed anddeployed state. This element can be configured to go into the deployedstate upon the application of a voltage and then return to thenon-deployed state upon the removal of the voltage. This and relatedembodiments allow for a reciprocating motion of the actuating mechanismso as to both advance the tissue penetrating member and then withdrawit.

The release element is coupled to at least one of the actuatingmechanism or a spring coupled to the actuating mechanism. In particularembodiments, the release element is coupled to a spring positionedwithin the capsule so as to retain the spring in a compressed state.Degradation of the release element releases the spring to actuate theactuation mechanism. In many embodiments, the release element comprisesa material configured to degrade upon exposure to chemical conditions inthe small or large intestine such as pH. Typically, the release elementis configured to degrade upon exposure to a selected pH in the smallintestine, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 8.0 or greater. However, itcan also be configured to degrade in response to other conditions in thesmall intestine. In particular embodiments, the release element can beconfigured to degrade in response to particular chemical conditions inthe fluids in the small intestine such as those which occur afteringestion of a meal (e.g., a meal high in fats or proteins).

Biodegradation of the release element from one or more conditions in thesmall intestine (or other location in the GI tract) can be achieved byselection of the materials for the release element, the amount of crosslinking of those materials as well as the thickness and other dimensionsof the release elements. Lesser amounts of cross linking and or thinnerdimensions can increase the rate of degradation and visa versa. Suitablematerials for the release element can comprise biodegradable materialssuch as various enteric materials which are configured to degrade uponexposure to the higher pH or other condition in the small intestine. Theenteric materials can be copolymerized or otherwise mixed with one ormore polymers to obtain a number of particular material properties inaddition to biodegradation. Such properties can include withoutlimitation stiffness, strength, flexibility and hardness.

In particular embodiments, the release element can comprise a film orplug that fits over or otherwise blocks the guide tube and retains thetissue penetrating member inside the guide tube. In these and relatedembodiments, the tissue penetrating member is coupled to a spring loadedactuating mechanism such that when the release element is degradedsufficiently, it releases the tissue penetrating member which thensprings out of the guide tube to penetrate into the intestinal wall. Inother embodiments, the release element can be shaped to function as alatch which holds the tissue penetrating element in place. In these andrelated embodiments, the release element can be located on the exterioror the interior of the capsule. In the interior embodiments, the capsuleand guide tubes are configured to allow for the ingress of intestinalfluids into the capsule interior to allow for the degradation of therelease element.

In some embodiments, the actuating mechanism can be actuated by means ofa sensor, such as a pH or other chemical sensor which detects thepresence of the capsule in the small intestine and sends a signal to theactuating mechanism (or to an electronic controller coupled to theactuating mechanism to actuate the mechanism). Embodiments of a pHsensor can comprise an electrode-based sensor or it can be amechanically-based sensor such as a polymer which shrinks or expandsupon exposure to the pH or other chemical conditions in the smallintestine. In related embodiments, an expandable/contractable sensor canalso comprise the actuating mechanism itself by using the mechanicalmotion from the expansion or contraction of the sensor.

According to another embodiment for detecting that the device is in thesmall intestine (or other location in the GI tract), the sensor cancomprise a strain gauge or other pressure/force sensor for detecting thenumber of peristaltic contractions that the capsule is being subject towithin a particular location in the intestinal tract. In theseembodiments, the capsule is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Thesmall intestine has between 12 to 9 contractions per minute with thefrequency decreasing down the length of the intestine. Thus, accordingto one or more embodiments detection of the number of peristalticcontractions can be used to not only determine if the capsule is in thesmall intestine but the relative location within the intestine as well.

As an alternative or supplement to internally activated drug delivery,in some embodiments, the user may externally activate the actuatingmechanism to deliver drug by means of RF, magnetic or other wirelesssignaling means known in the art. In these and related embodiments, theuser can use a handheld device (e.g., a hand held RF device) which notonly includes signaling means, but also means for informing the userwhen the device is in the small intestine or other location in the GItract. The later embodiment can be implemented by including an RFtransmitter on the swallowable device to signal to the user when thedevice is in the small intestine or other location (e.g., by signalingan input from the sensor). The same handheld device can also beconfigured to alter the user when the actuating mechanism has beenactivated and the selected drug(s) delivered. In this way, the user isprovided confirmation that the drug has been delivered. This allows theuser to take other appropriate drugs/therapeutic agents as well as makeother related decisions (e.g., for diabetics to eat a meal or not andwhat foods should be eaten). The handheld device can also be configuredto send a signal to the swallowable device to over-ride the actuatingmechanism and so prevent, delay or accelerate the delivery of drug. Inuse, such embodiments allow the user to intervene to prevent, delay oraccelerate the delivery of drug based upon other symptoms and/or patientactions (e.g., eating a meal, deciding to go to sleep, exercise etc).

The user may also externally activate the actuating mechanism at aselected time period after swallowing the capsule. The time period canbe correlated to a typical transit time or range of transit times forfood moving through the user's GI tract to a particular location in thetract such as the small intestine.

Another aspect of the inventions provides therapeutic agent preparationsfor delivery into the wall of the small intestine (or other wall in theintestinal tract) using embodiments of the swallowable device describedherein. The preparation comprises a therapeutically effective dose of atleast one therapeutic agent. It may comprise a solid, liquid orcombination of both and can include one or more pharmaceuticalexcipients. The preparation has a shape and material consistency to becontained in embodiments of the swallowable capsule, delivered from thecapsule into the intestinal wall and degrade within the wall to releasethe dose of therapeutic agent. The preparation may also have aselectable surface area to volume ratio so as enhance or otherwisecontrol the rate of degradation of the preparation in the wall of thesmall intestine or other body lumen. In various embodiments, thepreparation can be configured to be coupled to an actuator such as arelease element or actuation mechanism which has a first configurationin which the preparation is contained in the capsule and a secondconfiguration in which the preparation is advanced out of the capsuleand into the wall of the small intestine. The dose of the drug or othertherapeutic agent in the preparation can be titrated downward from thatwhich would be required for conventional oral delivery methods so thatpotential side effects from the drug can be reduced.

Typically, though not necessarily, the preparation will be shaped andotherwise configured to be contained in the lumen of a tissuepenetrating member, such as a hollow needle which is configured to beadvanced out of the capsule and into the wall of the small intestine.The preparation itself may comprise a tissue penetrating memberconfigured to be advanced into the wall of the small intestine or otherlumen in the intestinal tract.

Another aspect of the invention provides methods for the delivery ofdrugs and the therapeutic agents into the walls of the GI tract usingembodiments of the swallowable drug delivery devices. Such methods canbe used for the delivery of therapeutically effective amounts of avariety of drugs and other therapeutic agents. These include a number oflarge molecule peptides and proteins which would otherwise requireinjection due to chemical breakdown in the stomach e.g., growth hormone,parathyroid hormone, insulin, interferons and other like compounds.Suitable drugs and other therapeutic agents which can be delivered byembodiments of invention include various chemotherapeutic agents (e.g.,interferon), antibiotics, antivirals, insulin and related compounds,glucagon like peptides (e.g., GLP-1, exenatide), parathyroid hormones,growth hormones (e.g., IFG and other growth factors), anti-seizureagents, immune suppression agents and anti-parasitic agents such asvarious anti-malarial agents. The dosage of the particular drug can betitrated for the patient's weight, age, condition or other parameter.

In various method embodiments, embodiments of the drug swallowable drugdelivery device can be used to deliver a plurality of drugs for thetreatment of multiple conditions or for the treatment of a particularcondition (e.g., a mixture of protease inhibitors for treatment HIVAIDS). In use, such embodiments allow a patient to forgo the necessityof having to take multiple medications for a particular condition orconditions. Also, they provide a means for facilitating that a regimenof two or more drugs is delivered and absorbed into the small intestineand thus, the blood stream at about the same time. Due to differences inchemical makeup, molecular weight, etc, drugs can be absorbed throughthe intestinal wall at different rates, resulting in differentpharmacokinetic distribution curves. Embodiments of the inventionaddress this issue by injecting the desired drug mixtures at about thesame time. This in turn improves pharmacokinetics and thus, the efficacyof the selected mixture of drugs.

Further details of these and other embodiments and aspects of theinvention are described more fully below, with reference to the attacheddrawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is a lateral viewing showing an embodiment of a swallowable drugdelivery device.

FIG. 1b is a lateral viewing showing an embodiment of a system includinga swallowable drug delivery device.

FIG. 1c is a lateral viewing showing an embodiment of a kit including aswallowable drug delivery device and a set of instructions for use.

FIG. 1d is a lateral viewing showing an embodiment of a swallowable drugdelivery device including a drug reservoir.

FIG. 2 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism foradvancing tissue penetrating members into tissue.

FIG. 3 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism having afirst motion converter.

FIG. 4 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism havingfirst and a second motion converter.

FIG. 5 is a perspective view illustrating engagement of the first andsecond motion converters with the tissue penetrating member and deliverymembers.

FIG. 6 is a cross sectional view illustrating an embodiment of theswallowable drug delivery device having a single tissue penetratingmember and an actuating mechanism for advancing the tissue penetratingmember.

FIG. 7a is a cross sectional view illustrating an embodiment of theswallowable drug delivery device having multiple tissue penetratingmembers and an actuating mechanism for advancing the tissue penetratingmembers.

FIG. 7b is a cross sectional view illustrating deployment of the tissuepenetrating members of the embodiment of FIG. 7a to deliver medicationto a delivery site and anchor the device in the intestinal wall duringdelivery.

FIGS. 8a-8c are side view illustrating positioning of the drug deliverydevice in the small intestine and deployment of the tissue penetratingmembers to deliver drug; FIG. 8a shows the device in the small intestineprior to deployment of the tissue penetrating members with the releaseelement in tact; FIG. 8b shows the device in the small intestine withthe release element degraded and the tissue penetrating elementsdeployed; and FIG. 8c shows the device in the small intestine with thetissue penetrating elements retracted and the drug delivered.

FIG. 9a shows an embodiment of a swallowable drug delivery deviceincluding a capsule having bio-degradable seams positioned to producecontrolled degradation of the capsule in the GI tract.

FIG. 9b shows the embodiment of FIG. 9a after having been degraded inthe GI tract into smaller pieces.

FIG. 10 shows an embodiment of a capsule having biodegradable seamsincluding pores and/or perforations to accelerate biodegradation of thecapsule.

FIG. 11 is a lateral viewing illustrating use of an embodiment of aswallowable drug delivery device including transit of device in the GItract and operation of the device to deliver drug.

FIGS. 12a and 12b are lateral view illustrating an embodiment of acapsule for the swallowable drug delivery device including a cap and abody coated with pH sensitive biodegradable coatings, FIG. 12a shows thecapsule in an unassembled state and FIG. 12b in an assembled state

FIGS. 13a and 13b illustrate embodiments of unfolded multi balloonassemblies containing a deployment balloon, an aligner balloon, adelivery balloon and assorted connecting tubes; FIG. 13a shows anembodiment of the assembly for a single dome configuration of thedeployment balloon; and FIG. 13b shows an embodiment of the assembly fordual dome configuration of the deployment balloon; and.

FIG. 13c is a perspective views illustrating embodiments of a nestedballoon configuration which can be used for one or more embodiments ofthe balloons described herein including the aligner balloon.

FIGS. 14a-14c are lateral views illustrating embodiments of a multicompartment deployment balloon; FIG. 14a shows the balloon in anon-inflated state with the separation valve closed; FIG. 14b shows theballoon with valve open and mixing of the chemical reactants; and FIG.14c shows the balloon in an inflated state.

FIGS. 15a-15g are lateral views illustrating a method for folding of themultiple balloon assembly, the folding configuration in each figureapplies to both single and dual dome configurations of the deploymentballoon, with the exception that FIG. 15c , pertains to a folding stepunique to dual dome configurations; and FIG. 15d , pertains to the finalfolding step unique to dual dome configurations; FIG. 15e , pertains toa folding step unique to single dome configurations; and FIGS. 15f and15g are orthogonal views pertaining to the final folding step unique tosingle dome configurations.

FIGS. 16a and 16b are orthogonal views illustrating embodiments of thefinal folded multi balloon assembly with the attached delivery assembly.

FIGS. 17a and 17b are orthogonal transparent views illustratingembodiments of the final folded multi balloon assembly inserted into thecapsule.

FIG. 18a is a side view of an embodiment of the tissue penetratingmember.

FIG. 18b is a bottom view of an embodiment of the tissue penetratingmember illustrating placement of the tissue retaining features.

FIG. 18c is a side view of an embodiment of the tissue penetratingmember having a trocar tip and inverted tapered shaft.

FIG. 18d is a side view of an embodiment of the tissue penetratingmember having a separate drug containing section.

FIGS. 18e and 18f are side views showing assembly of an embodiment of atissue penetrating member having a shaped drug containing section. FIG.18e shows the tissue penetrating member and shaped drug section prior toassembly; and FIG. 18f after assembly.

FIG. 19 provides assorted views of the components and steps used toassemble an embodiment of the delivery assembly.

FIGS. 20a-20i provides assorted views illustrating a method of operationof swallowabe device to deliver medication to the intestinal wall.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the invention provide devices, systems and methods fordelivering medications in to various locations in the body. As usedherein, the term “medication” refers to a medicinal preparation in anyform which can include drugs or other therapeutic agents as well as oneor more pharmaceutical excipients. Many embodiments provide aswallowable device for delivering medication within the GI tract.Particular embodiments provide a swallowable device such as a capsulefor delivering medications to the wall of the small intestine or otherGI organ. As used herein, “GI tract” refers to the esophagus, stomach,small intestine, large intestine and anus, while “Intestinal tract”refers to the small and large intestine. Various embodiments of theinvention can be configured and arranged for delivery of medication intothe intestinal tract as well as the entire GI tract.

Referring now to FIGS. 1-11, an embodiment of an device 10 for thedelivery of medication 100 to a delivery site DS in the intestinal tractsuch as the wall of the small intestine, comprises a capsule 20including at least one guide tube 30, one or more tissue penetratingmembers 40 positioned or otherwise advanceable in the at least one guidetube, a delivery member 50, an actuating mechanism 60 and releaseelement 70. Medication 100, also described herein as preparation 100,typically comprises at least one drug or therapeutic agent 101 and mayinclude one or more pharmaceutical excipients known in the art.Collectively, one or more of delivery member 50 and mechanism 60 maycomprise a means for delivery of medication 100 into a wall of theintestinal tract. Other delivery means contemplated herein include oneor more expandable balloons (e.g., delivery balloon 172) or otherexpandable device/member described herein.

Device 10 can be configured for the delivery of liquid, semi-liquid orsolid forms of medication 100 or all three. Solid forms ofmedication/preparation 100 can include both powder or pellet. Semiliquid forms can include a slurry or paste. Whatever the form,preparation 100 desirably has a shape and material consistency allowingthe medication to be advanced out of the device, into the intestinalwall (or other luminal wall in the GI tract) and then degrade in theintestinal wall to release the drug or other therapeutic agent 101. Thematerial consistency can include one or more of the hardness, porosityand solubility of the preparation (in body fluids). The materialconsistency can be achieved by one or more of the following: i) thecompaction force used to make the preparation; ii) the use of one ormore pharmaceutical disintegrants known in the art; iii) use of otherpharmaceutical excipients; iv) the particle size and distribution of thepreparation (e.g., micronized particles); and v) use of micronizing andother particle formation methods known in the art. Suitable shapes forpreparation 100 can include cylindrical, cubical, rectangular, conical,spherical, hemispherical and combinations thereof. Also, the shape canbe selected so as to define a particular surface area and volume ofpreparation 100 and thus, the ratio between the two. The ratio ofsurface area to volume can in turn, be used to achieve a selected rateof degradation within the intestinal or other lumen wall within the GItract. Larger ratios (e.g., larger amounts of surface area per unitvolume) can be used to achieve faster rates of degradation and viceversa. In particular embodiments, the surface area to volume ratio canbe in the range of about 1:1 to 100:1, with specific embodiments of 2:1,5:1, 20:1, 25:1, 50:1 and 75:1. Preparation/medication 100 willtypically be pre-packed within a lumen 44 of tissue penetrating members40, but can also be contained at another location within an interior 24of capsule 20, or in the case of a liquid or semi-liquid, within anenclosed reservoir 27. The medication can be pre-shaped to fit into thelumen or packed for example, in a powder form. Typically, the device 10will be configured to deliver a single drug 101 as part of medication100. However in some embodiments, the device 10 can be configured fordelivery of multiple drugs 101 including a first second, or a third drugwhich can be compounded into a single or multiple medications 100. Forembodiments having multiple medications/drugs, the medications can becontained in separate tissue penetrating members 40 or within separatecompartments or reservoirs 27 within capsule 20. In another embodiment,a first dose 102 of medication 100 containing a first drug 101 can bepacked into the penetrating member(s) 40 and a second dose 103 ofmedication 100 (containing the same or a different drug 101) can becoated onto the surface 25 of capsule as is shown in the embodiment ofFIG. 1b . The drugs 101 in the two doses of medication 102 and 103 canbe the same or different. In this way, a bimodal pharmacokinetic releaseof the same or different drugs can be achieved. The second dose 103 ofmedication 100 can have an enteric coating 104 to ensure that it isreleased in the small intestine and achieve a time release of themedication 100 as well. Enteric coating 104 can include one or moreenteric coatings described herein or known in the art.

A system 11 for delivery of medication 100 into the wall of the smallintestine or other location within the GI tract, may comprise device 10,containing one or more medications 100 for the treatment of a selectedcondition or conditions. In some embodiments, the system may include ahand held device 13, described herein for communicating with device 10as is shown in the embodiment of FIG. 1b . System 11 may also beconfigured as a kit 14 including system 11 and a set of instructions foruse 15 which are packaged in packaging 12 as is shown in the embodimentof FIG. 1c . The instructions can indicate to the patient when to takethe device 10 relative to one or more events such as the ingestion of ameal or a physiological measurement such as blood glucose, cholesterol,etc. In such embodiments, kit 14 can include multiple devices 10containing a regimen of medications 100 for a selected period ofadministration, e.g., a day, week, or multiple weeks depending upon thecondition to be treated.

Capsule 20 is sized to be swallowed and pass through the intestinaltract. The size can also be adjusted depending upon the amount of drugto be delivered as well as the patient's weight and adult vs. pediatricapplications. Capsule 20 includes an interior volume 24 and an outersurface 25 having one or more apertures 26 sized for guide tubes 30. Inaddition to the other components of device 10, (e.g., the actuationmechanism etc.) the interior volume can include one or more compartmentsor reservoirs 27. One or more portions of capsule 20 can be fabricatedfrom various biocompatible polymers known in the art, including variousbiodegradable polymers which in a preferred embodiment can comprise PLGA(polylactic-co-glycolic acid). Other suitable biodegradable materialsinclude various enteric materials described herein as well as lactide,glycolide, lactic acid, glycolic acid, para-dioxanone, caprolactone,trimethylene carbonate, caprolactone, blends and copolymers thereof. Asis described in further detail herein, in various embodiments, capsule20 can include seams 22 of bio-degradable material so as to controllablydegrade into smaller pieces 23 which are more easily passed through theintestinal tract. Additionally, in various embodiments, the capsule caninclude various radio-opaque or echogenic materials for location of thedevice using fluoroscopy, ultrasound or other medical imaging modality.In specific embodiments, all or a portion of the capsule can includeradio-opaque/echogenic markers 20 m as is shown in the embodiment ofFIGS. 1a and 1b . In use, such materials not only allow for the locationof device 10 in the GI tract, but also allow for the determination oftransit times of the device through the GI tract.

In preferred embodiments, tissue penetrating members 40 are positionedwithin guide tubes 30 which serve to guide and support the advancementof members 40 into tissue such as the wall of the small intestine orother portion of the GI tract. The tissue penetrating members 40 willtypically comprise a hollow needle or other like structure and will havea lumen 44 and a tissue penetrating end 45 for penetrating a selectabledepth into the intestinal wall IW. Member 40 may also include a pin 41for engagement with a motion converter 90 described herein. The depth ofpenetration can be controlled by the length of member 40, theconfiguration of motion converter 90 described herein as well as theplacement of a stop or flange 40 s on member 40 which can, in anembodiment, correspond to pin 41 described herein. Medication 100 willtypically be delivered into tissue through lumen 44. In manyembodiments, lumen 44 is pre-packed with the desired medication 100which is advanced out of the lumen using delivery member 50 or otheradvancement means (e.g. by means of force applied to a collapsibleembodiment of member 40). As an alternative, medication 100 can beadvanced into lumen 44 from another location/compartment in capsule 20.In some embodiments, all or a portion of the tissue penetrating member40 can be fabricated from medication 100 itself. In these and relatedembodiments, the medication can have a needle or dart-like structure(with or without barbs) configured to penetrate and be retained in theintestinal wall, such as the wall of the small intestine. The dart canbe sized and shaped depending upon the medication, dose and desireddepth of penetration into the intestinal wall. Medication 100 can beformed into darts, pellets or other shapes using various compressionmolding methods known in the pharmaceutical arts.

In various embodiments, device 10 can include a second 42 and a third 43tissue penetrating member 40 as is shown in the embodiments of FIGS. 7aand 7b ., with additional numbers contemplated. Each tissue penetratingmember 40 can be used to deliver the same or a different medication 100.In preferred embodiments, the tissue penetrating members 40 can besubstantially symmetrically distributed around the perimeter 21 ofcapsule 20 so as to anchor the capsule onto the intestinal wall IWduring delivery of medications 100. Anchoring capsule 20 in such a wayreduces the likelihood that the capsule will be displaced or moved byperistaltic contractions occurring during delivery of the medication. Inspecific embodiments, the amount of anchoring force can be adjusted tothe typical forces applied during peristaltic contraction of the smallintestine. Anchoring can be further facilitated by configured some orall of tissue penetrating members 40 to have a curved or arcuate shape.

Delivery member 50 is configured to advance medication 100 through thetissue penetrating member lumen 44 and into the intestinal wall IW.Accordingly, at least a portion of the delivery member 50 is advanceablewithin the tissue penetrating member lumen 44 and thus member 50 has asize and shape (e.g., a piston like shape) configured to fit within thedelivery member lumen 44.

In some embodiments, the distal end 50 d of the delivery member (the endwhich is advanced into tissue) can have a plunger element 51 whichadvances the medication within the tissue penetrating member lumen 44and also forms a seal with the lumen. Plunger element 51 can be integralor attached to delivery member 50. Preferably, delivery member 50 isconfigured to travel a fixed distance within the needle lumen 44 so asto deliver a fixed or metered dose of drug into the intestinal wall IW.This can be achieved by one or more of the selection of the diameter ofthe delivery member (e.g., the diameter can be distally tapered), thediameter of the tissue penetrating member (which can be narrowed at itsdistal end), use of a stop, and/or the actuating mechanism. However insome embodiments, the stroke or travel distance of member 50 can beadjusted in situ responsive to various factors such as one or moresensed conditions in the GI tract. In situ adjustment can be achievedthrough use of logic resource 29 (including controller 29 c) coupled toan electro-mechanical embodiment of actuating mechanism 60. This allowsfor a variable dose of medication and/or variation of the distance themedication is injected into the intestinal wall.

Actuating mechanism 60 can be coupled to at least one of the tissuepenetrating member 40 or delivery member 50. The actuating mechanism isconfigured to advance tissue penetrating member 40 a selectable distanceinto the intestinal wall IW as well as advance the delivery member todeliver medication 100 and then withdraw the tissue penetrating memberfrom the intestinal wall. In various embodiments, actuating mechanism 60can comprise a spring loaded mechanism which is configured to bereleased by release element 70. Suitable springs 80 can include bothcoil (including conical shaped springs) and leaf springs with otherspring structures also contemplated. In particular embodiments, spring80 can be substantially cone-shaped to reduce the length of the springin the compressed state even to the point where the compressed length ofthe spring is about the thickness of several coils (e.g., two or three)or only one coil.

In particular embodiments actuating mechanism 60 can comprise a spring80, a first motion converter 90, and a second motion converter 94 and atrack member 98 as is shown in the embodiments of FIGS. 2, 4 and 8 a-8c. The release element 70 is coupled to spring 80 to retain the springin a compressed state such that degradation of the release elementreleases the spring. Spring 80 may be coupled to release element 70 by alatch or other connecting element 81. First motion converter 90 isconfigured to convert motion of spring 80 to advance and withdraw thetissue penetrating member 40 in and out of the intestinal wall or othertissue. The second motion converter 94 is configured to convert motionof the spring 80 to advance the delivery member 50 into the tissuepenetrating member lumen 44. Motion converters 90 and 94 are pushed bythe spring and ride along a rod or other track member 98 which fits intoa track member lumen 99 of converter 90. The track member 98 serves toguide the path of the converters 90. Converters 90 and 94 engage thetissue penetrating member 40 and/or delivery member 50 (directly orindirectly) to produce the desired motion. They have a shape and othercharacteristics configured to convert motion of the spring 80 along itslongitudinal axis into orthogonal motion of the tissue penetratingmember 40 and/or delivery member 50 though conversion in otherdirections is also contemplated. The motion converters can have a wedge,trapezoidal or curved shape with other shapes also contemplated. Inparticular embodiments, the first motion converter 90 can have atrapezoidal shape 90 t and include a slot 93 which engages a pin 41 onthe tissue penetrating member that rides in the slot as is shown in theembodiments of FIGS. 2, 3 and 4. Slot 93 can also have a trapezoidalshape 93 t that mirrors or otherwise corresponds to the overall shape ofconverter 90. Slot 93 serves to push the tissue penetrating member 40during the upslope portion 91 of the trapezoid and then pull it backduring the down slope portion 92. In one variation, one or both of themotion converters 90 and 94 can comprise a cam or cam like device (notshown). The cam can be turned by spring 80 so as to engage the tissuepenetrating and/or delivery members 40 and 50. One or more components ofmechanism 60 (as well as other components of device 10) including motionconverters 90 and 94 can be fabricated using various MEMS-based methodsknown in the art so as to allow for selected amounts of miniaturizationto fit within capsule 10. Also as is described herein, they can beformed from various biodegradable materials known in the art.

In other variations, the actuating mechanism 60 can also comprise anelectro-mechanical device/mechanism such as a solenoidor a piezoelectricdevice. In one embodiment, a piezoelectric device used in mechanism 60can comprise a shaped piezoelectric element which has a non-deployed anddeployed state. This element can be configured to go into the deployedstate upon the application of a voltage and then return to thenon-deployed state upon the removal of the voltage or other change inthe voltage. This and related embodiments allow for a reciprocatingmotion of the actuating mechanism 60 so as to both advance the tissuepenetrating member and then withdraw it. The voltage for thepiezoelectric element can be obtained generated using a battery or apiezoelectric based energy converter which generates voltage bymechanical deformation such as that which occurs from compression of thecapsule 20 by a peristaltic contraction of the small intestine aroundthe capsule. Further description of piezoelectric based energyconverters is found in U.S. patent application Ser. No. 12/556,524 whichis fully incorporated by reference herein for all purposes. In oneembodiment, deployment of tissue penetrating members 40 can in fact betriggered from a peristaltic contraction of the small intestine whichprovides the mechanical energy for generating voltage for thepiezoelectric element.

Release element 70 will typically be coupled to the actuating mechanism60 and/or a spring coupled to the actuating mechanism; however, otherconfigurations are also contemplated. In preferred embodiments, releaseelement 70 is coupled to a spring 80 positioned within capsule 20 so asto retain the spring in a compressed state 85 as shown in the embodimentof FIG. 2. Degradation of the release element 70 releases spring 80 toactuate actuation mechanism 60. Accordingly, release element 70 can thusfunction as an actuator 70 a (actuator 70 may also include spring 80 andother elements of mechanism 60). As is explained further below, releaseelement 70/actuator 70 a has a first configuration where the therapeuticagent preparation 100 is contained within capsule 20 and a secondconfiguration where the therapeutic agent preparation is advanced fromthe capsule into the wall of the small intestine or other luminal wallin the intestinal tract.

In many embodiments, release element 70 comprises a material configuredto degrade upon exposure to chemical conditions in the small or largeintestine such as pH. Typically, release element 70 is configured todegrade upon exposure to a selected pH in the small intestine, e.g.,7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6 8.0 or greater. The release elementcan also be configured to degrade within a particular range of pH suchas, e.g., 7.0 to 7.5. In particular embodiments, the pH at which releaseelement 70 degrades (defined herein as the degradation pH) can beselected for the particular drug to be delivered so as to release thedrug at a location in small intestine which corresponds to the selectedpH. Further, for embodiments of device 10 having multiple medications100, the device can include a first release element 70 (coupled to anactuating mechanism for delivering a first drug) configured to degradeat first pH and a second release element 70 (coupled to an actuatingmechanism for delivering a second drug) configured to degrade at asecond pH (with additional numbers of release elements contemplated forvarying number of drugs).

Release element 70 can also be configured to degrade in response toother conditions in the small intestine (or other GI location). Inparticular embodiments, the release element 70 can be configured todegrade in response to particular chemical conditions in the fluids inthe small intestine such as those which occur after ingestion of a meal(e.g., a meal containing fats, starches or proteins). In this way, therelease of medication 100 can be substantially synchronized or otherwisetimed with the digestion of a meal.

Various approaches are contemplated for biodegradation of releaseelement 70. In particular embodiments, biodegradation of release element70 from one or more conditions in the small intestine (or other locationin the GI tract) can be achieved by one or more of the followingapproaches: i) selection of the materials for the release element, ii)the amount of cross linking of those materials; and iii) the thicknessand other dimensions of the release element. Lesser amounts of crosslinking and or thinner dimensions can increase the rate of degradationand visa versa. Suitable materials for the release element can comprisebiodegradable materials such as various enteric materials which areconfigured to degrade upon exposure to the higher pH in the intestines.Suitable enteric materials include, but are not limited to, thefollowing: cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylicacid methyl esters as well as other enteric materials known in the art.The selected enteric materials can be copolymerized or otherwisecombined with one or more other polymers to obtain a number of otherparticular material properties in addition to biodegradation. Suchproperties can include without limitation stiffness, strength,flexibility and hardness.

In alternative embodiments, the release element 70 can comprise a filmor plug 70 p that fits over or otherwise blocks guide tubes 30 andretains the tissue penetrating member 40 inside the guide tube. In theseand related embodiments, tissue penetrating member 40 is coupled to aspring loaded actuating mechanism such that when the release element isdegraded sufficiently, it releases the tissue penetrating member whichthen springs out of the guide tube to penetrate into the intestinalwall. In still other embodiments, release element 70 can be shaped tofunction as a latch which holds the tissue penetrating member 40 inplace. In these and related embodiments, the release element can belocated on the exterior or the interior of capsule 20. In the lattercase, capsule 20 and/or guide tubes 30 can be configured to allow forthe ingress of intestinal fluids into the capsule interior to allow forthe degradation of the release element.

In some embodiments, actuating mechanism 60 can be actuated by means ofa sensor 67, such as a pH sensor 68 or other chemical sensor whichdetects the presence of the capsule in the small intestine. Sensor 67can then send a signal to actuating mechanism 60 or to an electroniccontroller 29 c coupled to actuating mechanism 60 to actuate themechanism. Embodiments of a pH sensor 68 can comprise an electrode-basedsensor or it can be a mechanically-based sensor such as a polymer whichshrinks or expands upon exposure to a selected pH or other chemicalconditions in the small intestine. In related embodiments, anexpandable/contractible sensor 67 can also comprise the actuatingmechanism 60 itself by using the mechanical motion from the expansion orcontraction of the sensor.

According to another embodiment for detecting that the device in thesmall intestine (or other location in the GI tract), sensor 67 cancomprise pressure/force sensor such as strain gauge for detecting thenumber of peristaltic contractions that capsule 20 is being subject towithin a particular location in the intestinal tract (in suchembodiments capsule 20 is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Thesmall intestine has between 12 to 9 contractions per minute with thefrequency decreasing down the length of the intestine. Thus, accordingto one or more embodiments, detection of the number of peristalticcontractions can be used to not only determine if capsule 20 is in thesmall intestine, but the relative location within the intestine as well.In use, these and related embodiments allow for release of medication100 at a particular location in the small intestine.

As an alternative or supplement to internally activated drug delivery(e.g., using a release element and/or sensor), in some embodiments, theuser may externally activate the actuating mechanism 60 to delivermedication 100 by means of RF, magnetic or other wireless signalingmeans known in the art. In these and related embodiments, the user canuse a handheld communication device 13 (e.g., a hand held RF device suchas a cell phone) as is shown in the embodiment of FIG. 1b , to send areceive signals 17 from device 10. In such embodiments, swallowabledevice may include a transmitter 28 such as an RF transceiver chip orother like communication device/circuitry. Handheld device 13 may notonly includes signaling means, but also means for informing the userwhen device 10 is in the small intestine or other location in the GItract. The later embodiment can be implemented through the use of logicresources 29 (e.g., a processor 29) coupled to transmitter 28 to signalto detect and singe to the user when the device is in the smallintestine or other location (e.g., by signaling an input from thesensor). Logic resources 29 may include a controller 29 c (either inhardware or software) to control one or more aspects of the process. Thesame handheld device can also be configured to alert the user whenactuating mechanism 60 has been activated and the selected medication100 delivered (e.g., using processor 29 and transmitter 28). In thisway, the user is provided confirmation that medication 100 has beendelivered. This allows the user to take other appropriatedrugs/therapeutic agents as well as make other related decisions (e.g.,for diabetics to eat a meal or not and what foods should be eaten). Thehandheld device can also be configured to send a signal to swallowabledevice 10 to over-ride actuating mechanism 60 and so prevent delay oraccelerate the delivery of medication 100. In use, such embodimentsallow the user to intervene to prevent, delay or accelerate the deliveryof medication, based upon other symptoms and/or patient actions (e.g.,eating a meal, deciding to go to sleep, exercise etc). The user may alsoexternally activate actuating mechanism 60 at a selected time periodafter swallowing the capsule. The time period can be correlated to atypical transit time or range of transit times for food moving throughthe user's GI tract to a particular location in the tract such as thesmall intestine.

In particular embodiments, the capsule 20 can include seams 22 ofbiodegradable material which controllably degrade to produce capsulepieces 23 of a selectable size and shape to facilitate passage throughthe GI tract as is shown in the embodiment of FIGS. 10a and 10b . Seams22 can also include pores or other openings 22 p for ingress of fluidsinto the seam to accelerate biodegradation as is shown in the embodimentof FIG. 10. Other means for accelerating biodegradation of seams 22 caninclude pre-stressing the seam and/or including perforations 22 f in theseam as is also shown in the embodiment of FIG. 10. In still otherembodiments, seam 22 can be constructed of materials and/or have astructure which is readily degraded by absorption of ultrasound energy,e.g. high frequency ultrasound (HIFU), allowing the capsule to bedegraded into smaller pieces using externally or endoscopically (orother minimally invasive method) administered ultrasound.

Suitable materials for seams 22 can include one or more biodegradablematerials described herein such as PLGA, glycolic acid etc. Seams 22 canbe attached to capsule body 20 using various joining methods known inthe polymer arts such as molding, hot melt junctions, etc. Additionally,for embodiments of capsule 20 which are also fabricated frombiodegradable materials, faster biodegradation of seam 22 can beachieved by one or more of the following: i) fabricating the seam from afaster biodegrading material, ii) pre-stressing the seam, or iii)perforating the seam. The concept of using biodegradable seams 22 toproduce controlled degradation of a swallowable device in the GI tractcan also be applied to other swallowable devices such as swallowablecameras (or other swallowable imaging device) to facilitate passagethrough the GI tract and reduce the likelihood of such a device becomingstuck in the GI tract. Accordingly, embodiments of biodegradable seam 22can be adapted for swallowable imaging and other swallowable devices.

Another aspect of the invention provides methods for the delivery ofdrugs and other therapeutic agents (in the form of medication 100) intothe walls of the GI tract using one or more embodiments of swallowabledrug delivery device 10. An exemplary embodiment of such a method willnow be described. The described embodiment of drug delivery occurs inthe small intestine SI. However, it should be appreciated that this isexemplary and that embodiments of the invention can be used fordelivering drug in a number of locations in the GI tract including thestomach and the large intestine. For ease of discussion, the swallowabledrug delivery device 10 will sometimes be referred to herein as acapsule. As described above, in various embodiments, device 10 may bepackaged as a kit 11 within sealed packaging 12 that includes device 10and a set of instructions for use 15. If the patient is using a handhelddevice 13, the patient may be instructed to enter data into device 13either manually or via a bar code 18 (or other identifying indicia 18)located on the instructions 15 or packaging 12. If a bar code is used,the patient would scan the bar code using a bar code reader 19 on device13. After opening packaging 12, reading the instructions 15 and enteringany required data, the patient swallows an embodiment of the swallowabledrug delivery device 10. Depending upon the drug, the patient may takethe device 10 in conjunction with a meal (before, during or after) or aphysiological measurement. Capsule 20 is sized to pass through the GItract and travels through the patient's stomach S and into the smallintestine SI through peristaltic action as is embodied in device 10shown in the embodiment of FIG. 11. Once in the small intestine, therelease element 70 is degraded by the basic pH in the small intestine(or other chemical or physical condition unique to the small intestine)so as to actuate the actuating mechanism 60 and deliver medication 100into the wall of the small intestine SI according to one or moreembodiments of the invention. For embodiments including a hollow needleor other hollow tissue penetrating member 40, medication delivery iseffectuated by using the actuating mechanism 60 to advance the needle 40a selected distance into the mucosa of the intestinal wall IS, and thenthe medication is injected through the needle lumen 40 by advancement ofthe delivery member 50. The delivery member 50 is withdrawn and theneedle 40 is then withdrawn back within the body of the capsule (e.g. byrecoil of the spring) detaching from the intestinal wall. Forembodiments of device 10 having multiple needles, a second or thirdneedle 42, 43 can also be used to deliver additional doses of the samedrug or separate drugs 101. Needle advancement can be done substantiallysimultaneously or in sequence. In preferred embodiments that usemultiple needles, needle advancement can be done substantiallysimultaneously so as to anchor device 10 in the small intestine duringdrug delivery.

After medication delivery, device 10 then passes through the intestinaltract including the large intestine LI and is ultimately excreted. Forembodiments of the capsule 20 having biodegradable seams 22 or otherbiodegradable portions, the capsule is degraded in the intestinal tractinto smaller pieces to facilitate passage through and excretion from theintestinal tract as is shown in the embodiments of FIGS. 9a and 9b . Inparticular embodiments having biodegradable tissue penetratingneedles/members 40, should the needle get stuck in the intestinal wall,the needle biodegrades releasing the capsule 20 from the wall.

For embodiments of device 10 including a sensor 67, actuation ofmechanism 60 can be effectuated by the senor sending a signal toactuating mechanism 60 and/or a processor 29/controller 29 c coupled tothe actuating mechanism. For embodiments of device 10 including externalactuation capability, the user may externally activate actuatingmechanism 60 at a selected time period after swallowing the capsule. Thetime period can be correlated to a typical transit time or range oftransit times for food moving through the user's GI tract to aparticular location in the tract such as the small intestine.

One or more embodiments of the above methods can be used for thedelivery of preparations 100 containing therapeutically effectiveamounts of a variety of drugs and other therapeutic agents 101 to treata variety of diseases and conditions. These include a number of largemolecule peptides and proteins which would otherwise require injectiondue to chemical breakdown in the stomach. The dosage of the particulardrug can be titrated for the patient's weight, age or other parameter.Also the dose of drug 101 to achieve a desired or therapeutic effect(e.g., insulin for blood glucose regulation) when delivered by one ormore embodiments of the invention can be less than the amount requiredshould the drug have been delivered by conventional oral delivery (e.g.,a swallowable pill that is digested in the stomach and absorbed throughthe wall of the small intestine). This is due to the fact that there isno degradation of the drug by acid and other digestive fluids in thestomach and the fact that all, as opposed to only a portion of the drugis delivered into the wall of the small intestine (or other lumen in theintestinal tract, e.g., large intestine, stomach, etc.). Depending uponthe drug 101, the dose 102 delivered in preparation 100 can be in therange from 100 to 5% of a dose delivered by conventional oral delivery(e.g., a pill) to achieve a desired therapeutic effect (e.g., bloodglucose regulation, seizure regulation, etc.) with even lower amountscontemplated. The particular dose reduction can be titrated based uponthe particular drug, the condition to be treated, and the patient'sweight, age and condition. For some drugs (with known levels ofdegradation in the intestinal tract) a standard dose reduction can beemployed (e.g., 10 to 20%). Larger amounts of dose reduction can be usedfor drugs which are more prone to degradation and poor absorption. Inthis way, the potential toxicity and other side effects (e.g., gastriccramping, irritable bowel, hemorrhage, etc.) of a particular drug ordrugs delivered by device 10 can be reduced because the ingested dose islowered. This in turn, improves patient compliance because the patienthas reduction both in the severity and incidence of side effects.Additional benefits of embodiments employing dose reduction of drug 101include a reduced likelihood for the patient to develop a tolerance tothe drug (requiring higher doses) and, in the case of antibiotics, forthe patient to develop resistant strains of bacteria. Also, other levelsof dose reduction can be achieved for patients undergoing gastric bypassoperations and other procedures in which sections of the small intestinehave been removed or its working (e.g., digestive) length effectivelyshortened.

In addition to delivery of a single drug, embodiments of swallowabledrug delivery device 10 and methods of their use can be used to delivera plurality of drugs for the treatment of multiple conditions or for thetreatment of a particular condition (e.g., protease inhibitors fortreatment HIV AIDS). In use, such embodiments allow a patient to forgothe necessity of having to take multiple medications for a particularcondition or conditions. Also, they provide a means for facilitatingthat a regimen of two or more drugs is delivered and absorbed into thesmall intestine and thus, the blood stream, at about the same time. Dueto difference in chemical makeup, molecular weight, etc., drugs can beabsorbed through the intestinal wall at different rates, resulting indifferent pharmacokinetic distribution curves. Embodiments of theinvention address this issue by injecting the desired drug mixtures atsubstantially the same time. This in turn, improves the pharmacokineticsand thus the efficacy of the selected mixture of drugs. Additionally,eliminating the need to take multiple drugs is particularly beneficialto patients who have one or more long term chronic conditions includingthose who have impaired cognitive or physical abilities.

In various applications, embodiments of the above methods can be used todeliver preparations 100 including drugs and therapeutic agents 101 toprovide treatment for a number of medical conditions and diseases. Themedical conditions and diseases which can be treated with embodiments ofthe invention can include without limitation: cancer, hormonalconditions (e.g., hypo/hyper thyroid, growth hormone conditions),osteoporosis, high blood pressure, elevated cholesterol andtriglyceride, diabetes and other glucose regulation disorders, infection(local or septicemia), epilepsy and other seizure disorders,osteoporosis, coronary arrhythmia's (both atrial and ventricular),coronary ischemia anemia or other like condition. Still other conditionsand diseases are also contemplated.

In many embodiments, the treatment of the particular disease orcondition can be performed without the need for injecting the drug orother therapeutic agent (or other non-oral form of delivery such assuppositories) but instead, relying solely on the therapeutic agent(s)that is delivered into the wall of the small intestine or other portionof the GI tract. Similarly, the patient need not take conventional oralforms of a drug or other therapeutic agent, but again rely solely ondelivery into the wall of the small intestine using embodiments of theswallowable capsule. In other embodiments, the therapeutic agent(s)delivered into the wall of the small intestine can be delivered inconjunction with an injected dose of the agent(s). For example, thepatient may take a daily dose of therapetic agent using the embodimentsof the swallowable capsule, but only need take an injected dose everyseveral days or when the patient's condition requires it (e.g.,hyperglycemia). The same is true for therapeutic agents that aretraditionally delivered in oral form (e.g., the patient can take theswallowable capsule and take the conventional oral form of the agent asneeded). The dosages delivered in such embodiments (e.g., the swallowedand injected dose) can be titrated as needed (e.g., using standard doseresponse curve and other pharmacokinetic methods can be used todetermine the appropriate dosages). Also, for embodiments usingtherapeutic agents that can be delivered by conventional oral means, thedose delivered using embodiments of the swallowable capsule can betitrated below the dosage normally given for oral delivery of the agentsince there is little or no degradation of the agent within the stomachor other portion of the intestinal tract (herein again standard doseresponse curve and other pharmacokinetic methods can be applied).

Various groups of embodiments of preparation 100 containing one or moredrugs or other therapeutic agents 101 for the treatment of variousdiseases and conditions will now be described with references todosages. It should be appreciated that these embodiments, including theparticular therapeutic agents and the respective dosages are exemplaryand the preparation 100 can comprise a number of other therapeuticagents described herein (as well as those known in the art) that areconfigured for delivery into a luminal wall in the intestinal tract(e.g., the small intestinal wall) using various embodiments of device10. The dosages can be larger or smaller than those described and can beadjusted using one or more methods described herein or known in the art.

In a group of embodiments, therapeutic agent preparation 100 cancomprise a therapeutically effective dose of growth hormone for thetreatment of one or more growth disorders, as well as wound healing. Inone embodiment, preparation 100 can contain a therapeutically effectiveamount of growth hormone in the range of about 0.1-4 mg, with particularranges of 0.1-1, 1-4, 1-2, and 2-4 mg, with still larger rangescontemplated. The particular dose can be titrated based on one or moreof the following factors: i) the particular condition to be treated andits severity (e.g. stunted growth, vs. wound healing); ii) the patient'sweight; iii) the patients age; and iv) the frequency of dosage (e.g.daily vs. twice daily).

Drug delivery compositions and components of known drug delivery systemsmay be employed and/or modified for use in some embodiments of theinventions described herein. For example, micro-needles and othermicrostructures used for delivery of drugs through the skin surface withdrug patches may be modified and included within the capsules describedherein and used to instead deliver a drug preparation into a lumen wallof the gastrointestinal tract such as the wall of the small intestine.Suitable polymer micro-needle structures may be commercially availablefrom Corium of California, such as the MicroCor™ micro delivery systemtechnology. Other components of the MicroCor™ patch delivery systems,including drug formulations or components, may also be incorporated intothe capsules described herein. Alternatively, a variety of providers arecommercially available to formulate combinations of polymers or otherdrug-delivery matrices with selected drugs and other drug preparationcomponents so as to produce desired shapes (such as the releasabletissue-penetrating shapes described herein) having desirable drugrelease characteristics. Such providers may, for example, includeCorium, SurModics of Minnesota, BioSensors International of Singapore,or the like.

One advantage and feature of various embodiments of the therapeuticcompositions described herein is that the biologic (therapeutic peptideor protein) drug payload is protected from degradation and hydrolysis bythe action of peptidases and proteases in the gastrointestinal (GI)tract. These enzymes are ubiquitous throughout living systems. The GItract is especially rich in proteases whose function is to break downthe complex proteins and peptides in one's diet into smaller segmentsand release amino acids which are then absorbed from the intestine. Thecompositions described herein are designed to protect the therapeuticpeptide or protein from the actions of these GI proteases and to deliverthe peptide or protein payload directly into the wall of the intestine.There are two features in various embodiments of the compositionsdescribed herein which serve to protect the protein or peptide payloadfrom the actions of GI proteases. First, in certain embodiments, thecapsule shell, which contains the deployment engine and machinery, doesnot dissolve until it reaches the duodenal and sub-duodenal intestinalsegments, owing to the pH-sensitive coating on the outer surface of thecapsule which prevents its dissolution in the low pH of the stomach.Second, in certain embodiments, hollow maltose (or other appropriatepolymer) micro-spears contain the actual therapeutic peptide or protein;the maltose (or other polymer) micro-spears are designed to penetratethe intestine muscle as soon as the outer capsule shell dissolves; andthe micro-spears themselves slowly dissolve in the intestinal musclewall to release the drug payload. Thus, the peptide or protein payloadis not exposed to the actions of the GI proteases and therefore does notundergo degradation via proteolysis in the GI tract. This feature, inturn, contributes to the high % bioavailabilty of the therapeuticpeptide or protein.

As discussed above, embodiments described herein include therapeuticcompositions comprising somatostatin. Such compositions may alsocomprise a somatostatin analogue, such as octreotide. Such compositionsresult in the delivery of somatostatin or somatostatin analogue withdesirable pharmacokinetic properties. Suitable conditions for treatmentwith somatostatin or somatostatin analogue include treatment ofacromegaly, treatment of diarrhea and flushing episodes associated withcarcinoid syndrome, treatment of diarrhea in patients with vasoactiveintestinal peptide-secreting tumors, or treatment of any othersomatostatin-responsive condition. In this regard, pharmacokineticmetrics of note include C_(max), the peak plasma concentration of a drugafter administration; t_(max), the time to reach C_(max); and t_(1/2),the time required for the plasma concentration of the drug to reach halfits C_(max) value after having reached C_(max). These metrics can bemeasured using standard pharmacokinetic measurement techniques known inthe art. In one approach plasma samples may be taken at set timeintervals (e.g., one minute, five minutes, ½ hour, 1 hour, etc.)beginning and then after administration of the drug or other therapeuticagent either by use of a swallowable device or by non-vascularinjection. The concentration of the drug in plasma can then be measuredusing one or more appropriate analytical methods such as GC-Mass Spec,LC-Mass Spec, HPLC or various ELISA (Enzyme-linked immunosorbent assays)which can be adapted for the particular drug. A concentration vs. timecurve (also herein referred to as a concentration profile) can then bedeveloped using the measurements from the plasma samples. The peak ofthe concentration curve corresponds to C_(max) and the time at whichthis occurs corresponds to t_(max). The time in the curve where theconcentration reaches half its maximum value (i.e., C_(max)) afterhaving reached C_(max) corresponds to t_(1/2) this value is also knownas the elimination half-life of the drug. The start time fordetermination of C_(max) can be based on the time at which the injectionis made for the case on non-vascular injection and the point in time atwhich embodiments of the swallowable device advances one or more tissuepenetrating members (containing the drug) into the small intestine orother location in the GI tract (e.g., the large intestine). In the latercase, this time can determined using one or means including a remotecontrolled embodiment of the swallowable device which deploys the tissuepenetrating members into the intestine wall in response to an externalcontrol signal (e.g., an RF signal) or for an embodiment of theswallowable device which sends an RF or other signal detectable outsidethe body when the tissue penetrating members have been deployed. Othermeans for detection of tissue penetrating member deployment into thesmall intestine are contemplated such as one more medical imagingmodalities including for example, ultrasound or fluoroscopy. In any oneof these studies, appropriate animal models can be used for example,dog, pig, rat etc. in order to model the human pharmacokinetic response.

Thus, various embodiments provide a therapeutic composition (alsoreferred to herein as a preparation) comprising somatostatin or asomatostatin analogue. The composition is adapted for insertion into anintestinal wall after oral ingestion, wherein upon insertion, thecomposition releases somatostatin or a somatostatin analogue into thebloodstream from the intestinal wall to achieve a C_(max) faster than anextravascularly injected dose of the therapeutic agent that is to say,achieving a C_(max) for the inserted form of therapeutic agent in ashorter time period (e.g., a smaller t_(max)) than that for a dose ofthe therapeutic agent that is injected extravacularly Note, that thedose of somatostatin or a somatostatin analogue in the compositiondelivered into the intestinal wall and the dose delivered byextravascular injection, may, but need not, be comparable to achievethese results. In various embodiments, the composition is configured toachieve a t_(max) for somatostatin or a somatostatin analogue (e.g., byrelease of the somatostatin or a somatostatin analogue into thebloodstream from the intestinal wall, e.g., that of the small intestine)which is about 80%, or 50%, or 30%, or 20%, or 10% of a t_(max) for anextravascularly injected dose of the therapeutic agent. Such anextravascularly injected dose of somatostatin or a somatostatin analoguecan be, for example, a subcutaneous injection or an intramuscularinjection. In certain embodiments, the C_(max) attained by deliveringsomatostatin or a somatostatin analogue by insertion into the intestinalwall is substantially greater, such as 5, 10, 20, 30, 40, 50, 60, 70, 80or even a 100 times greater, than the C_(max) attained when somatostatinor a somatostatin analogue is delivered orally without insertion intothe intestinal wall for example by a pill other convention oral form ofsomatostatin or a somatostatin analogue. In some embodiments, thesomatostatin or a somatostatin analogue composition is configured toproduce a long-term release of somatostatin or a somatostatin analogue.Also, the composition can be configured to produce a long-term releaseof the therapeutic agent with a selectable t_(1/2). For example, theselectable t_(1/2) may be 6, or 9, or 12, or 15 or 18, or 24 hours.

In some embodiments, the therapeutic agent composition may also includea therapeutically effective dose of an incretin for the treatment ofdiabetes or a glucose regulation disorder. Incretins which can be usedinclude a glucagon-like peptide-1 (GLP-1), a GLP-1 analogue or a gastricinhibitory peptide (GIP). Exemplary GLP-1 analogues include exenatide,liraglutide, albiglutide and taspoglutide. Any appropriate dose of anincretin may be used; for example, exenatide may be used in a doseranging from about 1 to 10 micrograms; or liraglutide may be used in arange from about 1 to 2 mg.

Any appropriate dose of somatostatin or somatostatin analogue for aparticular patient may be used, depending on factors such as weight,age, etc. For example, the dose of the somastatin analogue octreotideadministered may range from about 10-100 μg, with particular ranges of20-80, 25-50 and 25-30 μg. When administered subcutaneously, octreotidetypically has a t_(max) in the bloodstream of about 30 minutes.Therefore, when administered in a therapeutic octreotide composition asdescribed herein, the t_(max) of the octreotide will be shortened, e.g.,to about 80%, or 50%, or 30%, or 20%, or 10% of the t_(max) foroctreotide when it is subcutaneously injected.

Another embodiment provides a therapeutic composition comprisingsomatostatin or somatostatin analogue, the composition adapted forinsertion into an intestinal wall after oral ingestion, wherein uponinsertion, the composition releases somatostatin or somatostatinanalogue into the blood stream from the intestinal wall to achieve at_(1/2) that is greater than a t_(1/2) for an orally ingested dose ofsomatostatin or somatostatin analogue that is not inserted into theintestinal wall. For example, the t_(1/2) of the dose inserted into theintestinal wall may be 100 or 50 or 10 or 5 times greater than the dosethat is not inserted into the intestinal wall.

The therapeutic somatostatin or somatostatin analogue composition may bein solid form, such as a solid form composition configured to degrade inthe intestinal wall, and the solid form composition may have, forexample, a tissue penetrating feature such as a pointed tip. Thetherapeutic somatostatin or somatostatin analogue composition maycomprise at least one biodegradable material and/or may comprise atleast one pharmaceutical excipient, including a biodegradable polymersuch as PGLA or a sugar such as maltose.

The therapeutic somatostatin or somatostatin analogue composition may bein solid form, such as a solid form composition configured to degrade inthe intestinal wall, and the solid form composition may have, forexample, a tissue penetrating feature such as a pointed tip. Thetherapeutic somatostatin or somatostatin analogue composition maycomprise at least one biodegradable material and/or may comprise atleast one pharmaceutical excipient, including a biodegradable polymersuch as PGLA or a sugar such as maltose.

In some embodiments, the therapeutic somatostatin or somatostatinanalogue composition may be configured to be delivered within a lumen ofa tissue penetrating member and/or the therapeutic somatostatin orsomatostatin analogue composition may be shaped as a tissue penetratingmember advanceable into the intestinal wall. The tissue penetratingmember may be sized to be completely contained within the intestinalwall, and/or it may include a tissue penetrating feature for penetratingthe intestinal wall, and/or it may include a retaining feature forretaining the tissue penetrating member within the intestinal wall. Theretaining feature may comprise, for example, a barb. In someembodiments, the tissue penetrating member is configured to be advancedinto the intestinal wall by the application of a force to a surface ofthe tissue penetrating member and, optionally, the tissue penetratingmember has sufficient stiffness to be advanced completely into theintestinal wall and/or the surface of the penetrating member isconfigured to be operatively coupled to an expandable balloon whichapplies the force upon expansion and/or the tissue penetrating member isconfigured to detach from a structure applying the force when adirection of the force changes.

Various aspects of the invention also provide other embodiments of aswallowable delivery device for the delivery of medication 100 inaddition to those described above. According to one or more suchembodiments, the swallow delivery device can include one or moreexpandable balloons or other expandable devices for use in deliveringone or more tissue penetrating members including medication 100 into thewall of an intestine, such as the small intestine. Referring now toFIGS. 12-20, another embodiment of a device 110 for the delivery ofmedication 100 to a delivery site DS in the gastro-intestinal (GI)tract, can comprise a capsule 120 sized to be swallowed and pass throughthe intestinal tract, a deployment member 130, one or more tissuepenetrating members 140 containing medication 100, a deployable aligner160 and a delivery mechanism 170. In some embodiments, medication 100(also referred to herein as preparation 100) may itself comprise tissuepenetrating member 140. The deployable aligner 160 is positioned withinthe capsule and configured to align the capsule with the intestine suchas the small intestine. Typically, this will entail aligning alongitudinal axis of the capsule with a longitudinal axis of theintestine; however, other alignments are also contemplated. The deliverymechanism 170 is configured for delivering medication 100 into theintestinal wall and will typically include a delivery member 172 such asan expandable member. The deployment member 130 is configured fordeploying at least one of the aligner 160 or the delivery mechanism 170.As will be described further herein, all or a portion of the capsulewall is degradable by contact with liquids in the GI tract so as toallow those liquids to trigger the delivery of medication 100 by device110. As used herein, “GI tract” refers to the esophagus, stomach, smallintestine, large intestine and anus, while “Intestinal tract” refers tothe small and large intestine. Various embodiments of the invention canbe configured and arranged for delivery of medication 100 into both theintestinal tract as well as the entire GI tract.

Device 110 including tissue penetrating member 140 can be configured forthe delivery of liquid, semi-liquid or solid forms of medication 100 orcombinations of all three. Whatever the form, medication 100 desirablyhas a material consistency allowing the medication to be advanced out ofdevice 110, into the intestinal wall (small or large intestine) or otherluminal wall in the GI tract and then degrade within the intestinal wallto release the drug or other therapeutic agent 101. The materialconsistency of medication 100 can include one or more of the hardness,porosity and solubility of the preparation (in body fluids). Thematerial consistency can be achieved by selection and use of one or moreof the following: i) the compaction force used to make the preparation;ii) the use of one or more pharmaceutical disintegrants known in theart; iii) use of other pharmaceutical excipients; iv) the particle sizeand distribution of the preparation (e.g., micronized particles); and v)use of micronizing and other particle formation methods known in theart.

Capsule 120 is sized to be swallowed and pass through the intestinaltract. The size can also be adjusted depending upon the amount of drugto be delivered as well as the patient's weight and adult vs. pediatricapplications. Typically, the capsule will have a tubular shape withcurved ends similar to a vitamin. In these and related embodiments,capsule lengths 120L can be in the range of 0.5 to 2 inches anddiameters 120D in the range of 0.1 to 0.5 inches with other dimensionscontemplated. The capsule 120 includes a capsule wall 121 w, having anexterior surface 125 and an interior surface 124 defining an interiorspace or volume 124 v. In some embodiments, the capsule wall 121 w caninclude one or more apertures 126 sized for the outward advancement oftissue penetrating members 140. In addition to the other components ofdevice 110, (e.g., the expandable member etc.) the interior volume caninclude one or more compartments or reservoirs 127.

The capsule can be fabricated from various biodegradable gelatinmaterials known in the pharmaceutical arts, but can also include variousenteric coatings 120 c, configured to protect the cap from degradationin the stomach (due to acids etc.), and then subsequently degrade in thein higher pH's found in the small intestine or other area of theintestinal tract. In various embodiments, the capsule 120 can be formedfrom multiple portions one or more of which may be biodegradable. Inmany embodiments, capsule 120 can be formed from two portions 120 p suchas a body portion 120 p″ (herein body 120 p″) and a cap portion 120 p′(herein cap 120 p), where the cap fits onto the body, e.g., by slidingover or under the body (with other arrangements also contemplated). Oneportion such as the cap 120 p′ can include a first coating 120 c′configured to degrade above a first pH (e.g., pH 5.5) and the secondportion such as the body 120 p″ can include a second coating 120 c″configured to degrade above a second higher pH (e.g. 6.5). Both theinterior 124 and exterior 125 surfaces of capsule 120 are coated withcoatings 120 c′ and 120 c″ so that that either portion of the capsulewill be substantially preserved until it contacts fluid having theselected pH. For the case of body 120 p″ this allows the structuralintegrity of the body 120 p″ to be maintained so as to keep balloon 172inside the body portion and not deployed until balloon 130 has expanded.Coatings 120 c′ and 120 c″ can include various methacrylate and ethylacrylate based coatings such as those manufactured by Evonik Industriesunder the trade name EUDRAGIT. These and other dual coatingconfigurations of the capsule 120 allows for mechanisms in one portionof capsule 120 to be actuated before those in the other portion of thecapsule. This is due to the fact that intestinal fluids will first enterthose portions where the lower pH coating has degraded thus actuatingtriggers which are responsive to such fluids (e.g., degradable valves).In use, such dual coating embodiments for capsule 120 provide fortargeted drug delivery to a particular location in the small intestine(or other location in the GI tract), as well as improved reliability inthe delivery process. This is due to the fact that deployment of aparticular component, such as aligner 160, can be configured to begin inthe upper area of the small intestine (e.g., the duodenum) allowing thecapsule to be aligned within the intestine for optimal delivery of thedrug (e.g., into the intestinal wall) as well as providing sufficienttime for deployment/actuation of other components to achieve drugdelivery into the intestinal wall while the capsule is still in thesmall intestine or other selected location.

As is discussed above, one or more portions of capsule 120 can befabricated from various biocompatible polymers known in the art,including various biodegradable polymers which in a preferred embodimentcan comprise cellulose, gelatin materials PLGA (polylactic-co-glycolicacid). Other suitable biodegradable materials include various entericmaterials described herein as well as lactide, glycolide, lactic acid,glycolic acid, para-dioxanone, caprolactone, trimethylene carbonate,caprolactone, blends and copolymers thereof.

In various embodiments, the wall 120 w of the capsule is degradable bycontact with liquids in the GI tract for example liquids in the smallintestine. In preferred embodiments, the capsule wall is configured toremain intact during passage through the stomach, but then to bedegraded in the small intestine. In one or more embodiments, this can beachieved by the use of an outer coating or layer 120 c on the capsulewall 120 w, which only degrades in the higher pH's found in the smallintestine and serves to protect the underlying capsule wall fromdegradation within the stomach before the capsule reaches the smallintestine (at which point the drug delivery process is initiated bydegradation of the coating as is described herein). In use, suchcoatings allow for the targeted delivery of a therapeutic agent in aselected portion of the intestinal tract such as the small intestine.

Similar to capsule 20, in various embodiments, capsule 120 can includevarious radio-opaque, echogenic or other materials for location of thedevice using one or more medical imaging modalities such as fluoroscopy,ultrasound, MM, etc.

As is discussed further herein, in many embodiments, one or more of thedeployment member 130, delivery member 172 or deployable aligner 160,may correspond to an expandable balloon that is shaped and sized to fitwithin capsule 120. Accordingly, for ease of discussion, deploymentmember 130, delivery member 172 and deployable aligner 160 will now bereferred to as balloon 130, 160 and 172; however, it should beappreciated that other devices including various expandable devices arealso contemplated for these elements and may include for example,various shape memory devices (e.g., an expandable basket made from shapememory biodegradable polymer spires), expandable piezo electric devices,and/or chemically expandable devices having an expanded shape and sizecorresponding to the interior volume 124 v of the capsule 120.

One or more of balloons 130, 160 and 172 can comprise various polymersknown in the medical device arts. In preferred embodiments such polymerscan comprise one or more types of polyethylene (PE) which may correspondto low density PE(LDPE), linear low density PE (LLDPE), medium densityPE (MDPE) and high density PE (HDPE) and other forms of polyethyleneknown in the art. In one more embodiments using polyethylene, thematerial may be cross-linked using polymer irradiation methods known inthe art so. In particular embodiments radiation-based cross-linking maybe used as to control the inflated diameter and shape of the balloon bydecreasing the compliance of the balloon material. The amount orradiation may be selected to achieve a particular amount of crosslinking to in turn produce a particular amount of compliance for a givenballoon, e.g., increased irradiation can be used to produce stiffer lesscompliant balloon material. Other suitable polymers can include PET(polyethylene teraphalate), silicone and polyurethane. In variousembodiments balloons 130, 160 and 172 may also include variousradio-opaque materials known in the art such as barium sulfate to allowthe physician to ascertain the position and physical state of theballoon (e.g., un-inflated, inflated or punctures. Balloons 130, 160 and172 can be fabricated using various balloon blowing methods known in theballoon catheters arts (e.g., mold blowing, free blowing, etc.) to havea shape and size which corresponds approximately to the interior volume124 v of capsule 120. In various embodiments one or more of balloons130, 160 and 172 and various connecting features (e.g., connectingtubes) can have a unitary construction being formed from a single mold.Embodiments employing such unitary construction provide the benefit ofimproved manufacturability and reliability since fewer joints must bemade between one or more components of device 110.

Suitable shapes for balloons 130, 160 and 172 include variouscylindrical shapes having tapered or curved end portions (an example ofsuch a shape including a hot dog). In some embodiments, the inflatedsize (e.g., diameter) of one or more of balloons 130, 160 and 172, canbe larger than capsule 120 so as to cause the capsule to come apart fromthe force of inflation, (e.g., due to hoop stress). In other relatedembodiments, the inflated size of one or more of balloons 130, 160 and172 can be such that when inflated: i) the capsule 120 has sufficientcontact with the walls of the small intestine so as to elicit aperistaltic contraction causing contraction of the small intestinearound the capsule, and/or ii) the folds of the small intestine areeffaced to allow. Both of these results allow for improved contactbetween the capsule/balloon surface and the intestinal wall so asdeliver tissue penetrating members 40 over a selected area of thecapsule and/or delivery balloon 172. Desirably, the walls of balloons130, 160 and 172 will be thin and can have a wall thickness in the rangeof 0.005 to 0.0001″ more preferably, in the range of 0.005 to 0.0001,with specific embodiments of 0.004, 0.003, 0.002, 0.001, and 0.0005).Additionally in various embodiments, one or more of balloon 130, 160 or172 can have a nested balloon configuration having an inflation chamber1601C and extended finger 160EF as is shown in the embodiments of FIG.13c . The connecting tubing 163, connecting the inflation chamber 1601Ccan be narrow to only allow the passage of gas 168, while the connectingtubing 36 coupling the two halves of balloon 130 can be larger to allowthe passage of water.

As indicated above, the aligner 160 will typically comprise anexpandable balloon and for ease of discussion, will now be referred toas aligner balloon 160 or balloon 160. Balloon 160 can be fabricatedusing materials and methods described above. It has an unexpanded andexpanded state (also referred to as a deployed state). In its expandedor deployed state, balloon 160 extends the length of capsule 120 suchthat forces exerted by the peristaltic contractions of the smallintestine SI on capsule 120 serve to align the longitudinal axis 120LAof the capsule 120 in a parallel fashion with the longitudinal axis LAIof the small intestine SI. This in turn serves to align the shafts oftissue penetrating members 140 in a perpendicular fashion with thesurface of the intestinal wall IW to enhance and optimize thepenetration of tissue penetrating members 140 into the intestinal wallIW. In addition to serving to align capsule 120 in the small intestine,aligner 160 is also configured to push delivery mechanism 170 out ofcapsule 120 prior to inflation of delivery balloon 172 so that thedelivery balloon and/or mechanism is not encumbered by the capsule. Inuse, this push out function of aligner 160 improves the reliability fordelivery of the therapeutic agent since it is not necessary to wait forparticular portions of the capsule (e.g., those overlying the deliverymechanism) to be degraded before drug delivery can occur.

Balloon 160 may be fluidically coupled to one or more components ofdevice 110 including balloons 130 and 172 by means of polymer tube orother fluidic couplings 162 which may include a tube 163 for couplingballoons 160 and 130 and a tube 164 for coupling balloon 160 and balloon172. Tube 163 is configured to allow balloon 160 to be expanded/inflatedby pressure from balloon 130 (e.g., pressure generated the mixture ofchemical reactants within balloon 130) and/or otherwise allow thepassage of liquid between balloons 130 and 160 to initiate a gasgenerating chemical reaction for inflation of one or both of balloons130 and 160. Tube 164 connects balloon 160 to 172 so as to allow for theinflation of balloon 172 by balloon 160. In many embodiments, tube 164includes or is coupled to a control valve 155 which is configured toopen at a selected pressure so as to control the inflation of balloon172 by balloon 160. Tube 164 may thus comprise a proximal portion 164 pconnecting to the valve and a distal portion 164 d leading from thevalve. Typically, proximal and distal portions 164 p and 164 d will beconnected to a valve housing 158 as is described below.

Valve 155 may comprise a triangular or other shaped section 156 of amaterial 157 which is placed within a the chamber 158 c of a valvehousing 158 (alternately, it may be placed directly within tubing 164).Section 157 is configured to mechanically degrade (e.g., tears, shears,delaminates, etc.) at a selected pressure so as to allow the passage ofgas through tube 164 and/or valve chamber 158 c. Suitable materials 157for valve 155 can include bees wax or other form of wax and variousadhesives known in the medical arts which have a selectable sealingforce/burst pressure. Valve fitting 158 will typically comprise a thincylindrical compartment (made from biodegradable materials) in whichsection 156 of material 157 is placed (as is shown in the embodiment ofFIG. 13b ) so as to seal the walls of chamber 158 c together orotherwise obstruct passage of fluid through the chamber. The releasepressure of valve 155 can be controlled through selection of one or moreof the size and shape of section 156 as well as the selection ofmaterial 157 (e.g., for properties such as adhesive strength, shearstrength etc.). In use, control valve 155 allows for a sequencedinflation of balloon 160 and 172 such that balloon 160 is fully orotherwise substantially inflated before balloon 172 is inflated. This,in turn, allows balloon 160 to push balloon 172 along with the rest ofdelivery mechanism 170 out of capsule 120 (typically from body portion120 p′) before balloon 172 inflates so that deployment of tissuepenetrating members 140 is not obstructed by capsule 120. In use, suchan approach improves the reliability of the penetration of tissuepenetrating members 140 into intestinal wall IW both in terms ofachieving a desired penetration depth and delivering greater numbers ofthe penetrating members 140 contained in capsule 120 since theadvancement of the members into intestinal wall IW is not obstructed bycapsule wall 120 w.

As is describe above, the inflated length 1601 of the aligner balloon160 is sufficient to have the capsule 120 become aligned with thelateral axis of the small intestine from peristaltic contractions of theintestine. Suitable inflated lengths 1601 for aligner 160 can include arange between about ½ to two times the length 1201 of the capsule 120before inflation of aligner 160. Suitable shapes for aligner balloon 160can include various elongated shapes such as a hotdog like shape. Inspecific embodiments, balloon 160 can include a first section 160′ and asecond section 160″, where expansion of first section 160′ is configuredto advance delivery mechanism 170 out of capsule 120 (typically out ofand second section 160″ is used to inflate delivery balloon 172. Inthese and related embodiments, first and second sections 160′ and 160″can be configured to have a telescope-style inflation where firstsection 160′ inflates first to push mechanism 170 out of the capsule(typically from body portion 120 p′) and second section 160″ inflates toinflate delivery member 172. This can be achieve by configuring firstsection 160′ to have smaller diameter and volume than second section160″ such that first section 160′ inflates first (because of its smallervolume) and with second section 160″ not inflating until first section60′ has substantially inflated. In one embodiment, this can befacilitated by use of a control valve 155 (described above) connectingsections 160′ and 160″ which does not allow passage of gas into section160″ until a minimum pressure has been reached in section 160′. In someembodiments, the aligner balloon can contain the chemical reactantswhich react upon mixture with water or other liquid from the deployingballoon.

In many embodiments, the deployment member 130 will comprise anexpandable balloon, known as the deployment balloon 130. In variousembodiments, deployment balloon 30 is configured to facilitatedeployment/expansion of aligner balloon 160 by use of a gas, forexample, generation of a gas 169 from a chemical. The gas may begenerated by the reaction of solid chemical reactants 165, such as anacid 166 (e.g., citric acid) and a base 166 (e.g., potassiumbicarbonate, sodium bicarbonate and the like) which are then mixed withwater or other aqueous liquid 168. The amount of reactants can be chosenusing stoichiometric methods to produce a selected pressure in one ormore of balloons 130, 160 and 72. The reactants 165 and liquids can bestored separately in balloon 130 and 160 and then brought together inresponse to a trigger event, such as the pH conditions in the smallintestine. The reactants 165 and liquids 168 can be stored in eitherballoon, however in preferred embodiments, liquid 168 is stored inballoon 130 and reactants 165 in balloon 160. To allow for passage ofthe liquid 168 to start the reaction and/or the resulting gas 169,balloon 130 may be coupled to aligner balloon 160 by means of aconnector tube 163 which also typically includes a separation means 150such as a degradable valve 150 described below. For embodiments whereballoon 130 contains the liquid, tube 163 has sufficient diameter toallow for the passage of sufficient water from balloon 130 to balloon 60to produce the desired amount of gas to inflate balloon 160 as wellinflate balloon 172. Also when balloon 130 contains the liquid, one orboth of balloon 30 and tube 63 are configured to allow for the passageof liquid to balloon 160 by one or more of the following: i) thecompressive forced applied to balloon 130 by peristaltic contractions ofthe small intestine on the exposed balloon 130; and ii) wicking ofliquid through tube 163 by capillary action.

Tube 163 will typically include a degradable separation valve or otherseparation means 150 which separates the contents of balloon 130, (e.g.,water 158) from those of balloon 160 (e.g., reactants 165) until thevalve degrades. Valve 150 can be fabricated from a material such asmaltose, which is degradable by liquid water so that the valve opensupon exposure to water along with the various liquids in the digestivetract. It may also be made from materials that are degradable responsiveto the higher pH's found in the intestinal fluids such as methacrylatebased coatings. The valve is desirably positioned at location on tube163 which protrudes above balloon 130 and/or is otherwise sufficientexposed such that when cap 120 p′ degrades the valve 150 is exposed tothe intestinal liquids which enter the capsule. In various embodiments,valve 150 can be positioned to lie on the surface of balloon 130 or evenprotrude above it (as is shown in the embodiments of FIGS. 16a and 16b), so that is has clear exposure to intestinal fluids once cap 120 p′degrades. Various embodiments of the invention provide a number ofstructures for a separation valve 150, for example, a beam likestructure (where the valve comprises a beam that presses down on tube163 and/or connecting section 136), or collar type structure (where thevalve comprise a collar lying over tube 163 and/or connecting section136). Still other valve structures are also contemplated.

Balloon 130 has a deployed and a non-deployed state. In the deployedstate, the deployment balloon 130 can have a dome shape 130 d whichcorresponds to the shape of an end of the capsule. Other shapes 130 sfor the deployed balloon 130 are also contemplated, such as spherical,tube-shape, etc. The reactants 165 will typically include at least tworeactants 166 and 167, for example, an acid such as citric acid and abase such as sodium bicarbonate. Other reactants 165 including otheracids, e.g., ascetic acid and bases, e.g., sodium hydroxide are alsocontemplated. When the valve or other separation means 150 opens, thereactants mix in the liquid and produce a gas such as carbon dioxidewhich expands the aligner balloon 160 or other expandable member.

In an alternative embodiment shown in FIG. 13b , the deployment balloon130 can actually comprise a first and second balloon 130′ and 130″connected by a tube 36 or other connection means 136 (e.g., a connectingsection). Connecting tube 136 will typically include a separation valve150 that is degradable by a liquid as described above and/or a liquidhaving a particular pH such as basic pH found in the small intestine(e.g., 5.5 or 6.5). The two balloons 130′ and 130″ can each have a halfdome shape 130 hs allowing them to fit into the end portion of thecapsule when in the expanded state. One balloon can contain the chemicalreactant(s) 165 (e.g., sodium bicarbonate, citric acid, etc.) the otherthe liquid water 168, so that when the valve is degraded the twocomponents mix to form a gas which inflates one or both balloons 130′and 130″ and in turn, the aligner balloon 160.

In yet another alternative embodiment, balloon 130 can comprise amulti-compartment balloon 130 mc, that is formed or other constructed tohave multiple compartments 130 c. Typically, compartments 130 c willinclude at least a first and a second compartment 134 and 135 which areseparated by a separation valve 150 or other separation means 150 as isshown in the embodiment of FIG. 14a . In many embodiments, compartments134 and 135 will have at least a small connecting section 136 betweenthem which is where separation valve 150 will typically be placed. Aliquid 168, typically water, can be disposed within first compartment134 and one or more reactants 165 disposed in second compartment 135(which typically are solid though liquid may also be used) as is shownin the embodiment of FIG. 14a . When valve 150 opens (e.g., fromdegradation caused by fluids within the small intestine) liquid 168enters compartment 135 (or vice versa or both), the reactant(s) 165 mixwith the liquid and produce a gas 169 such as carbon dioxide whichexpands balloon 130 which in turn can be used to expand one or more ofballoons 160 and 172.

Reactants 165 will typically include at least a first and a secondreactant, 166 and 167 for example, an acid such as citric acid and abase such as sodium bi-carbonate or potassium bi-carbonate. As discussedherein, in various embodiments they may be placed in one or more ofballoon 130 (including compartments 134 and 135 or halves 130′ and 130″)and balloon 160. Additional reactants, including other combinations ofacids and bases which produce an inert gas by product are alsocontemplated. For embodiments using citric acid and sodium or potassiumbicarbonate, the ratio's between the two reactants (e.g., citric acid topotassium bicarbonate) can be in the range of about 1:1 to about 1:4,with a specific ratio of about 1:3. Desirably, solid reactants 165 havelittle or no absorbed water. Accordingly, one or more of the reactants,such as sodium bicarbonate or potassium bicarbonate can be pre-dried(e.g., by vacuum drying) before being placed within balloon 130. Otherreactants 165 including other acids, e.g., ascetic acid and bases arealso contemplated. The amounts of particular reactants 165, includingcombinations of reactants can be selected to produce particularpressures using known stoichiometric equations for the particularchemical reactions as well as the inflated volume of the balloon and theideal gas law (e.g., PV=nRT). In particular embodiments, the amounts ofreactants can be selected to produce a pressure selected one or more ofballoons 130, 160 and 172 to: i) achieve a particular penetration depthinto the intestinal wall; and produce a particular diameter for one ormore of balloons 130, 160 and 172; and iii) exert a selected amount offorce against intestinal wall IW. In particular embodiments, the amountand ratios of the reactants (e.g., citric acid and potassiumbicarbonate) can be selected to achieve pressures in one more of theballoons 130, 160 and 172 in the range of 10 to 15 psi, with smaller andlarger pressures contemplated. Again the amounts and ratio's of thereactants to achieve these pressures can be determined using knownstoichiometric equations.

In various embodiments of the invention using chemical reactants 165 togenerate gas 169, the chemical reactants alone or in combination withthe deployment balloon 130 can comprise a deployment engine for 180deploying one or both of the aligner balloon 160 and delivery mechanism170 including delivery balloon 172. Deployment engine 180 may alsoinclude embodiments using two deployment balloons 130 and 130″ (a dualdome configuration as shown in FIG. 13b ), or a multi compartmentballoon 130 mc as shown in FIG. 14a . Other forms of a deployment engine180 are also contemplated by various embodiments of the invention suchas use of expandable piezo-electric materials (that expand byapplication of a voltage), springs and other shape memory materials andvarious thermally expandable materials.

One or more of the expandable balloons 130, 160 and 172 will alsotypically include a deflation valve 159 which serves to deflate theballoon after inflation. Deflation valve 159 can comprise biodegradablematerials which are configured to degrade upon exposure to the fluids inthe small intestine and/or liquid in one of the compartments of theballoon so as to create an opening or channel for escape of gas within aparticular balloon. Desirably, deflation valves 159 are configured todegrade at a slower rate than valve 150 to allow sufficient time forinflation of balloons, 130, 160 and 172 before the deflation valvedegrades. In various embodiments, of a compartmentalized balloon 130,deflation valve 159 can correspond to a degradable section 139positioned on an end portion 131 of the balloon as is shown in theembodiment of FIG. 14a . In this and related embodiments, whendegradable section 139 degrades from exposure to the liquid, balloonwall 132 tears or otherwise comes apart providing for a high assuranceof rapid deflation. Multiple degradable sections 139 can be placed atvarious locations within balloon wall 132.

In various embodiments of balloon 172, deflation valve 159 cancorrespond to a tube valve 173 attached to the end 172 e of the deliveryballoon 172 (opposite to the end which is coupled to the alignerballoon) as is shown in the embodiment of FIG. 13b . The tube valve 173comprises a hollow tube 173 t having a lumen that is obstructed at aselected location 1731 with a material 173 m such as maltose thatdegrades upon exposure to fluid such as the fluid in the smallintestine. The location 1731 of the obstructing material 173 m in tube173 t is selected to provide sufficient time for the delivery balloon172 to inflate and deliver the tissue penetrating members 40 into theintestinal wall IW before the obstructing material dissolves to openvalve 173. Typically, this will be close to the end 173 e of the tube173 t, but not quite so as to allow time for liquid to have to wick intothe tube lumen before it reaches material 173 m. According to one ormore embodiments, once the deflation valve 173 opens, it not only servesto deflate the delivery balloon 172 but also the aligner balloon 160 anddeployment balloon 130 since in many embodiments, all three arefludicially connected (aligner balloon being fludically connected todelivery balloon 172 and the deployment balloon 130 being fludicallyconnected to aligner balloon 160). Opening of the deflation valve 173can be facilitated by placing it on the end 172 e of the deliveryballoon 172 that is forced out of capsule 120 by inflation of thealigner balloon 160 so that the deflation valve has good exposure toliquids in the small intestine. Similar tube deflation valves 173 canalso be positioned on one or both of aligner balloon 162 and thedeployment balloon 130. In these later two cases, the obstructingmaterial in the tube valve can be configured to degrade over a timeperiod to allow sufficient time for inflation of delivery balloon 172and advancement of tissue penetrating members 140 into the intestinalwall.

Additionally, as further backup for insured deflation, one or morepuncture elements 182 can be attached to the inside surface 124 of thecapsule such that when a balloon (e.g., balloon 130, 160, 172) fullyinflates it contacts and is punctured by the puncture element 182.Puncture elements 182 can comprise short protrusions from surface 124having a pointed tip. In another alternative or additional embodiment ofmeans for balloon deflation, one or more of the tissue penetratingmembers 140 can be directly coupled to the wall of 172 w of balloon 172and configured to tear away from the balloon when they detach, tearingthe balloon wall in the process.

A discussion will now be presented of tissue penetrating members 140.Tissue penetrating member 140 can be fabricated from various drugs andother therapeutic agents 101, one or more pharmaceutical excipients(e.g., disintegrants, stabilizers, etc.) and one or more biodegradablepolymers. The later materials chosen to confer desired structural andmaterial properties to the penetrating member (for example, columnstrength for insertion into the intestinal wall, or porosity andhydrophilicity for control the release of drug). Referring now to FIGS.18a-18f , in many embodiments, the penetrating member 140 can be formedto have a shaft 144 and a needle tip 145 or other pointed tip 145 so asto readily penetrate tissue of the intestinal wall as shown in theembodiment of FIG. 18a . In preferred embodiments, tip 145 has a trocarshape as is shown in the embodiment of FIG. 18c . Tip 145 may comprisevarious degradable materials (within the body of the tip or as acoating), such as sucrose or other sugar which increase the hardness andtissue penetrating properties of the tip. Once placed in the intestinalwall, the penetrating member 140 is degraded by the interstitial fluidswithin the wall tissue so that the drug or other therapeutic agent 101dissolves in those fluids and is absorbed into the blood stream. One ormore of the size, shape and chemical composition of tissue penetratingmember 140 can be selected to allow for dissolution and absorption ofdrug 101 in a matter of seconds, minutes or even hours. Rates ofdissolution can be controlled through the use of various disintegrantsknown in the pharmaceutical arts. Examples of disintegrants include, butare not limited to, various starches such as sodium starch glycolate andvarious cross linked polymers such as carboxymethyl cellulose. Thechoice of disintegrants can be specifically adjusted for the environmentwithin the wall of the small intestine.

Tissue penetrating member 140 will also typically include one or moretissue retaining features 143 such as a barb or hook to retain thepenetrating member within the tissue of the intestinal wall IW afteradvancement. Retaining features 143 can be arranged in various patterns143 p to enhance tissue retention such as two or more barbssymmetrically or otherwise distributed around and along member shaft 144as is shown in the embodiments of FIGS. 18a and 18b . Additionally, inmany embodiments, penetrating member will also include a recess or othermating feature 146 for attachment to a coupling component on deliverymechanism 170.

Tissue penetrating member 140 is desirably configured to be detachablycoupled to platform 175 (or other component of delivery mechanism 170),so that after advancement of the tissue penetrating member 140 into theintestinal wall, the penetrating member detaches from the balloon.Detachability can be implemented by a variety of means including: i) thesnugness or fit between the opening 174 in platform 175 and the membershaft 144); ii) the configuration and placement of tissue retainingfeatures 143 on penetrating member 140; and iii) the depth ofpenetration of shaft 144 into the intestinal wall. Using one or more ofthese factors, penetrating member 140 be configured to detach as aresult of balloon deflation (where the retaining features 143 hold thepenetrating member 140 in tissue as the balloon deflates or otherwisepulls back away from the intestinal wall) and/or the forces exerted oncapsule 120 by a peristaltic contraction of the small intestine.

In a specific embodiment, the detachability and retention of tissuepenetrating member 140 in the intestinal wall IW can be enhanced byconfiguring the tissue penetrating member shaft 144 to have an inversetaper 144 t as is shown in the embodiment of FIG. 18c . The taper 144 ton the shaft 144 is configured such that the application of peristalticcontractile forces from the intestinal wall on the shaft result in theshaft being forced inward (e.g., squeezed inward). This is due to theconversion by shaft taper 144 t of the laterally applied peristalticforce PF to an orthogonal force OF acting to force the shaft inward intothe intestinal wall. In use, such inverse tapered shaft configurationsserve to retain tissue penetrating member 140 within the intestinal wallso as to detach from platform 175 (or other component of deliverymechanism 170) upon deflation of balloon 172. In additional embodiments,tissue penetrating members 140 having an inverse tapered shaft may alsoinclude one or more retaining features 143 to further enhance theretention of the tissue penetrating member within intestinal wall IWonce inserted.

As described above, in various embodiments, tissue penetrating member140 can be fabricated from a number of drugs and other therapeuticagents 101. Also according to one or more embodiments, the tissuepenetrating member may be fabricated entirely from drug 101 or may haveother constituent components as well, e.g., various pharmaceuticalexcipients (e.g., binders, preservatives, disintegrants, etc.), polymersconferring desired mechanical properties, etc. Further, in variousembodiments one or more tissue penetrating members 140 can carry thesame or a different drug 101 (or other therapeutic agent) from othertissue penetrating members. The former configuration allows for thedelivery of greater amounts of a particular drug 101, while the later,allows two or more different drugs to be delivered into the intestinalwall at about the same time to facilitate drug treatment regimensrequiring substantial concurrent delivery of multiple drugs. Inembodiments of device 110, having multiple delivery assemblies 178(e.g., two, one on each face of balloon 172), a first assembly 178′ cancarry tissue penetrating members having a first drug 101 and a secondassembly 178″ can carry tissue penetrating members having a second drug101.

Typically, the drug or other therapeutic agent 101 carried by the tissuepenetrating member 140 will be mixed in with a biodegradable material105 to form tissue penetrating member 140. Material 105 may include oneor more biodegradable polymers such as PLGA, cellulose, as well assugars such as maltose or other biodegradable material described hereinor known in the art. In such embodiments, the penetrating member 140 maycomprise a substantially heterogeneous mixture of drug 101 andbiodegradable material 105. Alternatively, the tissue penetrating member140 may include a portion 141 formed substantially from biodegradablematerial 105 and a separate section 142 that is formed from or containsdrug 101 as shown in the embodiment of FIG. 18d . In one or moreembodiments, section 142 may correspond to a pellet, slug, cylinder orother shaped section 142 s of drug 101. Shaped section 142 s may bepre-formed as a separate section which is then inserted into a cavity142 c in tissue penetrating member 140 as is shown in the embodiments ofFIGS. 18e and 18f . Alternatively section 142 s may be formed by addingof drug preparation 100 to cavity 142 c. In embodiments, where drugpreparation 100 is added to cavity 142 c, preparation may be added in asa powder, liquid, or gel which is poured or injected into cavity 142 c.Shaped section 142 s may be formed of drug 101 by itself or a drugpreparation containing drug 101 and one or more binders, preservatives,disintegrates and other excipients. Suitable binders includepolyethylene glycol (PEG) and other binders known in the art. In variousembodiments, the PEG or other binder may comprise in the range of about10 to 90% weight percent of the section 142 s, with a preferredembodiment for insulin preparations of about 25-90 weight percent. Otherexcipients which may be used for binders may include PLA, PLGA,Cyclodextrin, Cellulose, Methyl Cellulose, maltose, Dextrin, Sucrose andPGA. Further information on the weight percent of excipients in section142 may be found in Table 1. For ease of discussion, section 142 isreferred to as a pellet in the table, but the data in the table is alsoapplicable to other embodiments of section 142 described herein.

In various embodiments, the weight of tissue penetrating member 140 canrange between about 10 to 15 mg, with larger and smaller weightscontemplated. For embodiments of tissue penetrating member 140fabricated from maltose, the weight can range from about 11 to 14 mg. Invarious embodiments, depending upon the drug 101 and the desireddelivered dose, the weight percent of drug in member 140 can range fromabout 0.1 to about 15%. In exemplary embodiments, these weight per centscorrespond to embodiments of members 140 fabricated from maltose orPLGA, however they are also applicable to any of the biodegradablematerials 105 used in the fabrication of members 140. The weight percentof drug or other therapeutic agent 101 in member 140 can be adjusteddepending upon the desired dose as well as to provide for structural andstoichiometric stability of the drug and also to achieve a desiredconcentration profile of the drug in the blood or other tissue of thebody. Various stability tests and models (e.g., using the Arrheniusequation) known in the art and/or known rates of drug chemicaldegradation may be used to make specific adjustments in the weightpercent range. Table 1 lists the dose and weight percent range forinsulin and number of other drugs which may be delivered by tissuepenetrating member 140. In some cases, the table lists ranges as well asingle value for the dose. It should be appreciated that these valuesare exemplary and other values recited herein including the claims arealso considered. Further, embodiments of the invention also considervariations around these values including for example, ±1, ±5, ±10, ±25,and even larger variations. Such variations are considered to fallwithin the scope of an embodiment claiming a particular value or rangeof values. The table also lists the weight percentage of drug in section142 for various drugs and other therapeutic agents, where again for easeof discussion, section 142 is referred to as a pellet. Again,embodiments of the invention consider the variations described above.

TABLE 1 % Weight of % Weight of Drug in drug in Drug Dose Via Capsule**the needle pellet Insulin 4-9 units, 5-30 units, 1-50 Units 2-15% 10-75%Exenatide 1-10 ug, 1-20 ug, 10 ug <1%, 0.1-1%  0.2-1% Liraglutide 0.1-1mg, 0.5-2 mg, 0.6 mg  3-6% 25-40% Pramlintide 15-120 ug 0.1-1%   0.5-6%Growth Hormone 0.2-1 mg, 0.1-4 mg 2-10% 10-50% Somatostatin and Analogs50-600 ug, 10-100 ug 0.3-8%   2-35% GnRH and Analogs 0.3-1.5 mg, 0.1-2mg 2-15% 15-75% Vasopressin 2-10 units <1%, 0.1-1%  0.2-1% PTH andAnalogues 0.1 to 10 ug, 10-30 ug, 20 ug  1-2%  0.5-2% Interferons andanalogs 1. For Multiple Sclerosis 0.03-0.25 mg 0.1-3%  1.5-15%  2. ForHep B and HepC 6-20 ug 0.05-0.2%     0.2-1% Adalimumab 1-5 mg, 2-4 mg8-12% 70-90% Infliximab 1-10, 5 mg 8-12% 70-90% Etanercept 1-5 mg, 3 mg8-12% 70-90% Natalizumab 1-5 mg, 3 mg 8-12% 70-90%

Tissue penetrating member 140 can be fabricated using one or morepolymer and pharmaceutical fabrication techniques known in the art. Forexample, drug 101 (with or without biodegradable material 105) can be insolid form and then formed into the shape of the tissue penetratingmember 140 using molding, compaction or other like method with one ormore binding agents added. Alternatively, drug 101 and/or drugpreparation 100 may be in solid or liquid form and then added to thebiodegradable material 105 in liquid form with the mixture then formedinto the penetrating member 140 using molding or other forming methodknown in the polymer arts.

Desirably, embodiments of the tissue penetrating member 140 comprising adrug or other therapeutic agent 101 and degradable material 105 areformed at temperatures which do not produce any substantial thermaldegradation of drug including drugs such as various peptides andproteins. This can be achieved through the use of room-temperaturecuring polymers and room temperature molding and solvent evaporationtechniques known in the art. In particular embodiments, the amount ofthermally degraded drug or other therapeutic agent within the tissuepenetrating member is desirably less than about 10% by weight and morepreferably, less than 5% and still more preferably less than 1%. Thethermal degradation temperature(s) for a particular drug are eitherknown or can be determined using methods known in the art and then thistemperature can be used to select and adjust the particular polymerprocessing methods (e.g., molding, curing. solvent evaporation methodsetc.) to minimize the temperatures and associated level of drug thermaldegradation.

A description will be provided of delivery mechanism 170. Typically, themechanism will comprise a delivery assembly 178 (containing tissuepenetrating members 140) that is attached to delivery balloon 172 as isshown in the embodiment of FIGS. 16a and 16b . Inflation of the deliveryballoon provides a mechanical force for engaging delivery assembly 172outwards from the capsule and into the intestinal wall IW so as toinsert tissue penetrating members 140 into the wall. In variousembodiments, the delivery balloon 172 can have an elongated shape withtwo relatively flat faces 172 f connected by an articulatedaccordion-like body 172 b. The flat faces 172 f can be configured topress against the intestinal wall (IW) upon expansion of the balloon 172so as to insert the tissue penetrating members (TPMs) 140 into theintestinal wall. TPMs 140 (either by themselves or as part of a deliveryassembly 178 described below) can be positioned on one or both faces 172f of balloon 172 to allow insertion of drug containing TPMs 40 onopposite sides of the intestinal wall. The faces 172 f of balloon 172may have sufficient surface area to allow for placement of a number ofdrug containing TPMs 140 on each face.

Referring now to FIG. 19, a description will now be provided of theassembly of delivery assembly 178. In a first step 300, one or moretissue penetrating members 140 can be detachably coupled to abiodegradable advancement structure 175 which may correspond to asupport platform 175 (also known as platform 175). In preferredembodiments, platform 175 includes one or more openings 174 forinsertion of members 140 as shown in step 300. Openings 174 are sized toallow for insertion and retention of members 140 in platform 175 priorto expansion of balloon 172 while allowing for their detachment from theplatform upon their penetration into the intestinal wall. Supportplatform 175 can then be positioned within a carrying structure 176 asshown in step 301. Carrying structure 176 may correspond to a wellstructure 176 having side walls 176 s and a bottom wall 176 b whichdefine a cavity or opening 176 c. Platform 175 is desirably attached toinside surface of bottom wall 176 b using adhesive or other joiningmethods known in the art. Well structure 176 can comprise variouspolymer materials and may be formed using vacuum forming techniquesknown in the polymer processing arts. In many embodiments, opening 176 ocan be covered with a protective film 177 as shown in step 302.Protective film 177 has properties selected to function as a barrier toprotect tissue penetrating members 140 from humidity and oxidation whilestill allowing tissue penetrating members 140 to penetrate the film asis described below. Film 177 can comprise various water and/or oxygenimpermeable polymers which are desirably configured to be biodegradablein the small intestine and/or to pass inertly through the digestivetract. It may also have a multi-ply construction with particular layersselected for impermeability to a given substance, e.g., oxygen, watervapor etc. In use, embodiments employing protective film 177 serve toincrease the shelf life of therapeutic agent 101 in tissue penetratingmembers 140, and in turn, the shelf life of device 110. Collectively,support platform 175 attached tissue penetrating members 140, wellstructure 176, and film 177 can comprise a delivery assembly 178.Delivery assemblies 178 having one or more drugs or therapeutic agents101 contained within tissue penetrating member 40 or other drug deliverymeans can be pre-manufactured, stored and subsequently used for themanufacture of device 110 at a later date. The shelf life of assembly178 can be further enhanced by filling cavity 176 c of the sealedassembly 178 with an inert gas such as nitrogen.

Referring back to FIGS. 16a and 16b , assemblies 178 can be positionedon one or both faces 172 f of balloon 172. In preferred embodiments,assemblies 178 are positioned on both faces 172 f (as shown in FIG. 16a) so as to provide a substantially equal distribution of force toopposite sides of the intestinal wall IW upon expansion of balloon 172.The assemblies 178 may be attached to faces 172 f using adhesives orother joining methods known in the polymer arts. Upon expansion ofballoon 172, TPMs 140 penetrate through film 177, enter the intestinalwall IW and are retained there by retaining elements 143 and/or otherretaining features of TPM 140 (e.g., an inverse tapered shaft 144 t)such that they detach from platform 175 upon deflation of balloon 172.

In various embodiments, one or more of balloons 130, 160 and 172 can bepacked inside capsule 120 in a folded, furled or other desiredconfiguration to conserve space within the interior volume 124 v of thecapsule. Folding can be done using preformed creases or other foldingfeature or method known in the medical balloon arts. In particularembodiments, balloon 130, 160 and 172 can be folded in selectedorientations to achieve one or more of the following: i) conserve space,ii) produce a desired orientation of a particular inflated balloon; andiii) facilitate a desired sequence of balloon inflations. Theembodiments shown in FIGS. 15a-15f illustrate an embodiment of a methodof folding and various folding arrangements. However, it should beappreciated that this folding arrangement and the resulting balloonorientations are exemplary and others may also be used. In this andrelated embodiments, folding can be done manually, by automated machineor a combination of both. Also in many embodiments, folding can befacilitated by using a single multi-balloon assembly 7 (herein assembly7) comprising balloons 130, 160, 170; valve chamber 158 and assortedconnecting tubings 162 as is shown in the embodiments of FIGS. 13a and13b . FIG. 13a shows an embodiment of assembly 7 having a single domeconstruction for balloon 130, while FIG. 13b shows the embodiment ofassembly 7 having dual balloon/dome configuration for balloon 130.Assembly 7 can be fabricated using a thin polymer film which isvacuum-formed into the desired shape using various vacuum forming andother related methods known in the polymer processing arts. Suitablepolymer films include polyethylene films having a thickness in the rangeof about 0.003 to about 0.010″, with a specific embodiment of 0.005″. Inpreferred embodiments, the assembly is fabricated to have a unitaryconstruction so as to eliminate the need for joining one or morecomponents of the assembly (e.g., balloons 130,160, etc.). However, itis also contemplated for assembly 7 to be fabricated from multipleportions (e.g., halves), or components (e.g., balloons) which are thenjoined using various joining methods known in the polymer/medical devicearts.

Referring now to FIGS. 15a-15f, 16a-16b and 17a-17b , in a first foldingstep 210, balloon 160 is folded over onto valve fitting 158 with balloon172 being flipped over to the opposite side of valve fitting 158 in theprocess (see FIG. 15a ). Then in step 211, balloon 172 is folded at aright angle to the folded combination of balloon 160 and valve 158 (seeFIG. 15b ). Then, in step 212 for dual dome embodiments of balloon 130,the two halves 130′ and 130″ of balloon 130 are folded onto each other,leaving valve 150 exposed (see FIG. 15c , for single dome embodiments ofballoon 130, is folded over onto itself see FIG. 15e ). A final foldingstep 213 can be done whereby folded balloon 130 is folded over 180° tothe opposite side of valve fitting 158 and balloon 160 to yield a finalfolded assembly 8 for dual dome configurations shown in the FIG. 15e anda final folded assembly 8′ for single dome configurations shown in FIGS.15e and 15f . One or more delivery assemblies 178 are then be attachedto assembly 8 in step 214 (typically two the faces 72 f of balloon 72)to yield a final assembly 9 (shown in the embodiments of FIGS. 16a and16b ) which is then inserted into capsule 120. After an insertion step215, the final assembled version of device 110 with inserted assembly 9is shown FIGS. 17a and 17 b.

Referring now to FIGS. 20a-20i , a description will be provided of amethod of using device 110 to deliver medication 101 to a site in the GItract such as the wall of the small or large intestine. It should beappreciated that the steps and there order is exemplary and other stepsand orders also contemplated. After device 110 enters the smallintestine SI, the cap coating 120 c′ is degraded by the basic pH in theupper small intestine causing degradation of cap 120 p′ as shown in step400 in FIG. 20b . Valve 150 is then exposed to fluids in the smallintestine causing the valve to begin degrade as is shown in step 401 inFIG. 20c . Then, in step 402, balloon 130 expands (due to generation ofgas 169) as shown in FIG. 20d . Then, in step 403, section 160′ ofballoon 160 begins to expand to start to push assembly 178 out of thecapsule body as shown in FIG. 20e . Then, in step 404, sections 160′ and160″ of balloon 160 become fully inflated to completely push assembly178 out of the capsule body extending the capsule length 1201 so as toserve to align capsule lateral axis 120AL with the lateral axis of thesmall intestine LAI as shown in FIG. 20f . During this time, valve 155is beginning to fail from the increased pressure in balloon 60 (due tothe fact that the balloon has fully inflated and there is no other placefor gas 169 to go). Then, in step 405, valve 155 has completely opened,inflating balloon 172 which then pushes the now completely exposedassembly 178 (having been pushed completely out of body 120 p″) radiallyoutward into the intestinal wall IW as shown in FIG. 20g . Then, in step406, balloon 172 continues to expand to now advance tissue penetratingmembers into the intestinal wall IW as shown in FIG. 20h . Then, in step407, balloon 172, (along with balloons 160 and 130) has deflated pullingback and leaving tissue penetrating members retained in the intestinalwall IW. Also, the body portion 120 p″ of the capsule has completelydegraded (due to degradation of coating 120 c″) along with otherbiodegradable portions of device 110. Any portion not degraded iscarried distally through the small intestine by peristaltic contractionfrom digestion and is ultimately excreted.

The foregoing description of various embodiments of the invention hasbeen presented for purposes of illustration and description. It is notintended to limit the invention to the precise forms disclosed. Manymodifications, variations and refinements will be apparent topractitioners skilled in the art. For example, embodiments of the devicecan be sized and otherwise adapted for various pediatric and neonatalapplications as well as various veterinary applications. Also thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificdevices and methods described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by theappended claims below.

Elements, characteristics, or acts from one embodiment can be readilyrecombined or substituted with one or more elements, characteristics oracts from other embodiments to form numerous additional embodimentswithin the scope of the invention. Moreover, elements that are shown ordescribed as being combined with other elements, can, in variousembodiments, exist as standalone elements. Hence, the scope of thepresent invention is not limited to the specifics of the describedembodiments, but is instead limited solely by the appended claims.

What is claimed is:
 1. A therapeutic preparation comprising somatostatinor somatostatin analogue, the preparation shaped as a solid tissuepenetrating member, the preparation configured to be contained in aswallowable capsule to penetrate and be inserted into an intestinal wallafter oral ingestion, wherein upon insertion, the preparation releasessomatostatin or somatostatin analogue into the blood stream from theintestinal wall.
 2. The therapeutic preparation of claim 1, wherein thepreparation releases the somatostatin or somatostatin analogue into theblood stream from the intestinal wall to achieve a C_(max) in a shortertime period than a time period to achieve a C_(max) for anextravascularly injected dose of somatostatin or somatostatin analogue.3. The therapeutic preparation of claim 1, wherein the C_(max) achievedby delivering the preparation by insertion into the intestinal wall issubstantially greater than a C_(max) achieved when the preparation isdelivered orally without insertion into the intestinal wall.
 4. Thetherapeutic preparation of claim 1, wherein a t_(max) for thesomatostatin or somatostatin analogue released from the therapeuticpreparation is about 80%, about 50%, or about 10% of a t_(max) for theextravascularly injected dose of somatostatin or somatostatin analogue.5. The therapeutic preparation of claim 1, wherein the extravascularinjection is a subcutaneous injection or an intramuscular injection. 6.The therapeutic preparation of claim 1, wherein the preparation isadapted to be operably coupled to delivery means having a firstconfiguration and a second configuration, the preparation beingcontained within the capsule in the first configuration and advanced outof the capsule and into the intestinal wall in the second configuration.7. The therapeutic preparation of claim 1, wherein the preparationcomprises a biodegradable material which degrades within the intestinalwall to release somatostatin or somatostatin analogue into the bloodstream.
 8. The therapeutic preparation of claim 1, wherein thepreparation comprises at least one pharmaceutical excipient.
 9. Thetherapeutic preparation of claim 1, wherein a weight percent ofsomatostatin or somatostatin analogue in the tissue penetrating membercomprises between about 0.3 to 8%.
 10. The therapeutic preparation ofclaim 1, wherein a dose of somatostatin or somatostatin analogue in thepreparation is in a range from about 50 to 600 mg.
 11. The therapeuticpreparation of claim 1, wherein the somatostatin analogue is octreotide.12. A method for delivering somatostatin or somatostatin analogue into awall of a gastrointestinal tract, the method comprising: configuring adrug delivery device to comprise a capsule, an actuator having a firstconfiguration and a second configuration, and a solid somatostatin orsomatostatin analogue preparation operably coupled to the actuator, thesolid somatostatin or somatostatin analogue preparation comprising atherapeutically effective dose of somatostatin or somatostatin analogue,the solid somatostatin or somatostatin analogue preparation beingcontained within the capsule in the first configuration and advancedinto the wall of the gastrointestinal tract in the second configuration,wherein the solid somatostatin or somatostatin analogue preparation hasa shape configured for penetration of the wall of the gastrointestinaltract; and providing the ingestible device to be swallowed by a patient.13. The method of claim 12, wherein a weight percent of somatostatincompound in the preparation is in a range between about 0.3 to 8%. 14.The method of claim 12, wherein a dose of somatostatin compound in thesomatostatin preparation is in a range from about 50 to 600 mg.
 15. Themethod of claim 12, wherein the somatostatin analogue is octreotide. 16.The method of claim 12, wherein the somatostatin or somatostatinanalogue preparation comprises at least one pharmaceutical excipient.17. The method of claim 12, wherein the somatostatin or somatostatinanalogue preparation treats a somatostatin responsive conditioncomprising acromegaly, diarrhea, diarrhea associated with carcinoidsyndrome, or diarrhea associated with vasoactive intestinalpeptide-secreting tumors.
 18. A method for delivering somatostatin orsomatostatin analogue into a wall of a gastrointestinal tract, themethod comprising: providing a capsule, an actuator having a firstconfiguration and a second configuration, and a solid somatostatin orsomatostatin analogue preparation that (i) comprises a therapeuticallyeffective dose of somatostatin or somatostatin analogue, (ii) isoperably coupled to the actuator, and (iii) is contained within thecapsule in the first configuration and is advanced into a wall of thegastrointestinal tract in the second configuration; and providing thecapsule to be swallowed.
 19. The method of claim 18, wherein a weightpercent of somatostatin compound in the preparation is in a rangebetween about 0.3 to 8%.
 20. The method of claim 18, wherein a dose ofsomatostatin compound in the somatostatin preparation is in a range fromabout 50 to 600 mg.
 21. The method of claim 18, wherein the somatostatinanalogue is octreotide.
 22. The method of claim 18, wherein thesomatostatin or somatostatin analogue preparation comprises at least onepharmaceutical excipient.
 23. The method of claim 18, wherein thesomatostatin or somatostatin analogue preparation treats a somatostatinresponsive condition comprising acromegaly, diarrhea, or diarrheaassociated with carcinoid syndrome, or diarrhea associated withvasoactive intestinal peptide-secreting tumors.